Clinical Studies Leading to Food and Drug Administration Approval

The results of the phase I trials paved the way for a phase II double-blind, randomized, placebo-controlled pilot trial conducted by Bornstein etal.31 The whole trial was executed without the backup of a pharmaceutical company. It was a National Institutes of Health-supported trial and the GA batches used in this trial were prepared and characterized in our laboratory. The study involved 50 patients with RRMS treated for 2 years by daily subcutaneous injections of either 20 mg GA or placebo....

Nonsteroidal Antiestrogens

Tamoxifen was not the first antiestrogen but the value of the drug slowly increased as the fashions in research changed. During the late 1950s and throughout the 1960s there was a focus on the development of new contraceptives in the wake of the success of oral contraceptives. These medicines did not treat a disease but altered lifestyle so there was huge potential for widespread use. But the application of antiestrogens as contraceptives failed and the compounds were drugs looking for a...

Insights Gained from Rigid Fused Ring Oxazolidinones

An area of major interest in my laboratory involved a series of novel tricyclic-fused oxazolidinones. Contrary to prior SAR conclusions that had been reported in the literature,24 we demonstrated that substitution could indeed be tolerated at both the ortho-phenyl and the oxazolidinone C-4 positions, provided these loci were connected with a short alkyl bridge in a trans orientation, relative to the 5-acetamidomethyl oxazolidinone side chain. My associate Peter Manninen initially synthesized...

Beta Blockers in Heart Failure Perspectives

The decision not to develop carvedilol for cardioprotection caused us to rethink what we could do with this very novel drug a drug unlike any other we had ever studied. We discussed the absurd possibility of studying carvedilol, a beta blocker, in congestive heart failure with a number of prominent cardiologists, and most were not interested in this prospect, and some were, quite frankly, astonished by such a radical proposal to use a contraindicated drug in such seriously ill patients. But we...

Reflections on Medicinal Chemistry Since the 1950s

H Timmerman, Vrije Universiteit, Amsterdam, The Netherlands 2007 Elsevier Ltd. All Rights Reserved. 8.02.2 Pharmacochemistry at the Vrije Universiteit Amsterdam 8.02.3 Being a Professor in Amsterdam 8.02.4 The 'New' Histamine Receptors 8.02.5 Histamine, Histamine Receptors, and Ligands as Research Tools When I started to study chemistry at the Vrije Universiteit in Amsterdam in 1956, it was just one hundred years since the history of modern synthetic medicines had started. Perkin had...

Patents

Scientists, especially medicinal chemists, should also take an enthusiastic interest in the patent work. Patents can be as important for the company as the compounds and drugs, and I believe that the effort put into the 'patent work' is not always as optimal as it should be. Patent work in pharmaceutical research has two quite different aspects the patent professional (attorney) and the scientific. A comparison can be made with the structure-activity relationship work, which also involves two...

Figure 2 Schematic of the mevalonate pathway All enzymes are listed in italics while metabolites are in bold The target

The variable that confers potency against FPP synthase relates to the position of the nitrogen group relative to the phosphonate groups. Interestingly, a modification in one of the phosphonate groups of risedronate, while drastically reducing FPP synthase inhibition, gave rise to a new compound with new activity against type II geranylgeranyl transferase.68 This derivative has substantially less antiresorptive activity than risedronate in vivo, likely due to reduced binding to bone.69 Other...

Incontinence Severity Index in SAAB

The fact that all efficacy measures showed improvements with duloxetine at all doses (but lacked statistical significance for all points) suggested that patients were really improving with duloxetine but that the small number of patients coupled with the noise in each of the individual parameters were obscuring the positive signal. Therefore, a factor analysis approach, the incontinence severity index (ISI), was developed by Ilker Yalcin.36'37 The underlying supposition in the creation of the...

References

HeartDisease and Stroke Statistics 2004 Update American Heart Association Dallas, TX, 2003. 2. Davidson, M. H. Toth, P. P Prog. Cardiovasc. Dis. 2004, 47, 73-104. 3. Dunbar, R. L. Rader, D. J. Drug Disc. Today 2004, 1, 169-176. 4. Bruckert, E. Cardiology 2002, 97, 59-66. 5. Shepherd, J. In 73rd European Atherosclerosis Society Congress, Salzburg, Austria, July 7, 2002. 6. Stein, E. Stender, S. Mata, P. Ponsonnet, D. Melani, L. Lipka, L. Suresh, R. Veltri, E. In 73rd...

Evidence for Molecular Mechanisms In Vivo

The molecular actions of the N-BPs, described above, have been confirmed in vivo using surrogate markers.80,81 In one study, the well-documented feedback regulation of HMG-CoA reductase expression by cholesterol biosynthetic intermediates was examined.80 ALN and other N-BPs, but not those lacking a nitrogen, suppressed expression of HMG-CoA reductase in osteoclasts from the proximal tibia. While ALN induced changes in HMG-CoA reductase expression in the osteoclast, no changes were seen in other...

Formation of the Oxazolidinone Working Group

The successful outcomes of the U-82965, U-97456, and U-85910 toxicology studies (as well as the poor performance of U-92300), gave us considerable confidence in our ability to use the 30 day toxicology protocol to identify oxazolidinone series most worthy of continued pursuit - and those unworthy of advancement due to an unacceptably low therapeutic index. The establishment of this knowledge basis contributed directly to the eventual increased support of the oxazolidinone project with the...

Introduction

The story of modafinil (Provigil), that began in the early 1970s, is the discovery of the unexpected activity of an NCE in classical animal models that transitioned to an effective agent that helped define and grow the field of sleep medicine. Additionally, extensive preclinical work on modafinil led to (1) the identification of additional therapeutic indications that were not fully appreciated from the initial in vivo profile for modafinil and (2) a continuing search, albeit unsuccessful, to...

Urge Urinary Incontinence and Overactive Bladder

Interestingly, the impetus for studying duloxetine was for discovering a treatment of urinary urge incontinence and overactive bladder. Insertion of EMG electrodes into the rhabdosphincter was a compulsion instilled in me during my dissertation studies to obtain as much data as practical from every experiment conducted. Even after seeing pronounced effects on the rhabdosphincter, I was still more impressed with the effects on the bladder and anticipated clinical benefits for urge incontinence...

Background and Introduction

The female sex hormone estrogen plays an essential role in reproduction and is important for the overall maintenance of physiologic homeostasis in a woman's body.1'2 During menopause, which occurs in women at an average age of 51, the amount of estrogen produced by the ovaries decreases and this estrogen deficiency causes menstrual periods to become less frequent and then stop.3-5 The loss of estrogen is responsible for many of the uncomfortable symptoms associated with menopause, including hot...

Creative Climate

My experiences of working with a number of creative people have led me to speculate about the determining factors that are the most important for cultivating a creative climate within a group of people. In my opinion, these are a suitable leadership (if there is a group leader), direct information, no hierarchy, no 'stolen' ideas, a high degree of openness, honesty, generosity, lack of prestige, and, finally, a sense of humor. Thus, it is important that all relevant information reaches the team...

Structure Activity Studies and the Struggle with Oral Bioavailability

Like renin and a number of other nonviral aspartic proteinases, the active site of HIV protease is lined principally with hydrophobic amino acids and encompasses approximately six amino acids (subsites P3 to P3'). Initial structure-activity relationship (SAR) studies with symmetry-based inhibitors indicated that the highest binding affinity could be achieved when all six subsites were occupied with hydrophobic amino acid side chains. Consequently, early inhibitor structures were large,...

The First Step The Discovery of Adrafinil

In the early 1970s, the Research Department of Laboratoire Louis Lafon, a small family-owned pharmaceutical company located in Maisons-Alfort, a suburb of Paris, had focused its research activities in three areas (1) cardiovascular (2) antispasmodics and (3) nonsteroidal anti-inflammatory drugs (NSAIDs) analgesics. In this last field, an empirical test battery was implemented, using the best-characterized in vivo pharmacological methods generally in use at that time (some of which are still...

P Lindberg Astra Zeneca RD Molndal Sweden 2007 Elsevier Ltd All Rights Reserved

8.17.1 My Early Years in Chemistry 213 8.17.1.1 My Thesis Work 213 8.17.1.2 My First Pharmaceutical Project 214 8.17.1.3 Moving to Goteborg to Work at the Department of Pharmacology 214 8.17.2 My Employment at Hassle 215 8.17.2.1 The Unique Action of Omeprazole 215 8.17.2.2 Omeprazole Prodrug for Parenteral Use 216 8.17.2.3 Esomeprazole - The Follow-Up 218 8.17.2.4 Reversible H+ ,K+-ATPase Inhibitors 219 8.17.2.5 Preclinical Alliances Group and Scientific Patent Support 220 8.17.3 Learning...

Biography

Per Lindberg graduated in organic chemistry from the University of Technology Lund, Sweden, in 1977 and was appointed Associate Professor of Organic Chemistry at the Chalmers Institute of Technology, Gothenburg, Sweden, in 1982. After working for several years with Prof Arvid Carlsson (Nobel Prize winner in Medicine, 2000) in the Department of Pharmacology, University of Gothenburg, he joined Hassle AB (today AstraZeneca R& D Molndal, Sweden) in 1982 as Head of Medicinal Chemistry GI and...

Immunological Properties of Glatiramer Acetate

Several immunological properties of GA are thought to contribute to the effects of GA. 8.14.4.1.1 Binding to major histocompatibility complex molecules GA exhibits a very rapid, high, and efficient binding to many different MHC class II haplotypes on living murine and human antigen-presenting cells (APCs). GA was also shown to interact with purified human leukocyte antigen (HLA)-DR molecules - DR1, DR2, and DR4 - with high affinity.45 As a result of its high and efficient binding to MHC class...

Oral study

Studies in laboratory models of EAE showed that oral administration of GA is effective in suppressing EAE in both rodents and primates in acute as well as chronic relapsing disease.15,16 In view of these results a double-blind and placebo-controlled study was initiated in RRMS patients. In this trial, given the code name Coral, two doses of oral GA, 5 and 50 mg respectively, or placebo, were given daily for 14 months, to 1650 MS patients enrolled from 158 sites in 18 different countries. The...

Conclusion

Adefovir dipivoxil (Hepsera) is an excellent example of a prodrug that can overcome the oral delivery problem associated with poor permeation across the intestinal mucosa. Since its launch in 2002, Hepsera has become an important agent for the treatment of hepatitis B patients with evidence of active viral replication. A safety profile similar to placebo has been observed for Hepsera, which allows it to be prescribed as an effective drug for chronic treatment of hepatitis B. 1. World Health...

Toxicity Issues

Adefovir dipivoxil 10mgday_ 1 has a safety profile that is similar to that of placebo30 and is well tolerated by healthy, renally, and hepatically impaired patients, as well as lamivudine-resistant HBV patients coinfected with HIV.31 A potential concern with adefovir dipivoxil is nephrotoxicity, which was observed at doses > 30 mg daily.32 This observation is consistent with the high clearance of adefovir which exceeds the glomerular filtration rate.5 Monitoring of renal function may be...

The Development of a Viable Synthesis of Oxazolidinones with High Enantiomeric Purity

At the beginning of our oxazolidinone exploratory project, we had elected to work with racemic compounds as a means of enabling the rapid SAR exploration and discovery of proprietary oxazolidinone series. The route we chose to the racemic oxazolidinones exploited an iodocyclocarbamation reaction, first developed by Fraser-Reid,37 and subsequently employed by others38'39 in a more closely related sense to our work. Our use of this iodine-mediated cyclization of N-allyl carbamates was the first...

Discovery of the Calcium Chemical a28 Binding Site

Important mechanism of action work began in about 1991 in the Parke-Davis Cambridge Research Centre. This work lead to the identification of a specific 3H gabapentin-binding site in rat brain tissues by David Hill, Nirmala Suman-Chauhan, and colleagues.5,71 They showed that the site was distributed heterogeneously in rat brain, with high densities of binding in regions that were also rich with synaptic endings. Later, Nicholas Gee and Jason Brown of the Cambridge Unit used protein biochemistry...

TSCZ thiosemicarbazide

Serendipitous finding by Satzinger eventually led to the identification of a new drug target and to two new effective therapies for the treatment of human disease. When compared to commonly used criteria to signal oral druglike properties, the physical characteristics of gabapentin, and its clinical successor pregabalin, are quite unique (Table 2). Both of these amino acids differ, particularly in their ClogP values as well as physical state at physiological pH when compared to most other...

Safety and Tolerability

Safety data accumulated from > 3500 MS patients treated with GA in controlled and uncontrolled studies indicate withdrawal from therapy for adverse experience in 8.4 .28 The most frequent reasons recorded for treatment withdrawals were dyspnea and vasodilation (2 for each). The most commonly reported adverse experiences are local injection site reactions which generally decline over time. They consist of erythema, pain, inflammation, pruritus, and swelling, but no skin necrosis. Localized...

Preclinical Alliances Group and Scientific Patent Support

In 1993 I took up a new position within the company, with responsibility for the Preclinical Alliances Group, covering both the gastrointestinal and cardiovascular areas. It was recognized that there was a need to map the external scientific community in a more systematic way and to bring more innovative projects and ideas into our exploratory preclinical research, both from universities and industry. The aim was to establish new scientific collaborations, which involved contacts with external...

Case

A major new perspective was learned in the 1970s and 1980s when therapeutic area teams of chemists, biologists, and clinicians were assigned to intervene in major disease conditions. Our understanding of mechanism, relevant animal models, and preferred points for disease intervention was very limited at that time. We made structural assumptions for prototypical compounds with known activity, synthesized a few grams from multistep pathways, tested this compound in several in vitro assays for...

The Discovery of Ezetimibe

While the data discussed so far provided encouragement that the activity of this class of compounds could be optimized, the absence of an in vitro assay made it difficult to separate potential effects on intrinsic potency from effects on pharmacokinetics. This issue was confounded by the fact that 14 is extensively metabolized in vivo, making Figure 14 Conformational model leading to design of spirocyclic compounds. the identity of the true active species unclear.13 To address this latter...

Adrenergic Receptors

SmithKline Beecham originally acquired rights to carvedilol in the US from Boehringer Mannhein (now part of Roche) with the obligation to develop the drug for angina and hypertension. The original pharmacological profile of carvedilol was that of a vasodilating beta blocker.1'2 A long-standing core team of scientists at SmithKline Beecham, consisting of the authors, as well as Hieble, Nichols and Ohlstein, devoted between one and two decades of their respective lives to understanding every...

Ch

This project formed an important part of the research within my department33 and I put considerable effort into it during the subsequent years. A number of CDs were selected but all of them were discontinued for potency, toxicological, or related reasons. In the mid-1990s, a few years after I left the Medicinal Chemistry Department, the unusually creative medicinal chemistry team of Ingemar Starke and co-workers returned to imidazolpyridines once more. The important, unexpected, 10-fold...

Science Medicine and Leadership Win Out The Pendulum Swings in Carvedilols Favor

Through the persistence and advocacy of the basic research team in Discovery and a small group of external heart failure leaders, the decision was made to undertake this extraordinary risk of resources (people and money, not to mention the potential liability) and initiate the clinical development of carvedilol in heart failure. In the end, science won out over historical bias. The data that swung the pendulum were extensive. Significant new science on the role of the activated adrenergic...

A R COMe 8b R 3pyridyl 8c R morpholinyl

This hypothesis would be in keeping with generalizations put forth by Brittelli and co-workers,24 which they derived from studies of multi-substitution about the oxazolidinone phenyl ring. From that work it was suggested that the oxazolidinone binding site was narrow, with limited space in what would be the general region of our tricyclic template central ring. They also noted that this narrow binding site appeared to possess a small pocket on one (undetermined) side of the linear axis...

Teitelbaum R Arnon and M Sela Weizmann Institute of Science Rehovot Israel 2007 Elsevier Ltd All Rights Reserved

8.14.2 Preclinical Studies 174 8.14.2.1 The Beginning 174 8.14.2.2 The Chemistry of Copaxone 175 8.14.2.3 Studies in Experimental Animal Models 175 8.14.3 Clinical Investigations 175 8.14.3.1 Early Clinical Trials 176 8.14.3.2 Clinical Studies Leading to Food and Drug Administration Approval 176 8.14.3.2.1 Bornstein study 176 8.14.3.2.2 Phase III studies 176 8.14.3.3 Recent Clinical Studies 176 8.14.3.3.1 Open-label extension of the American phase III trial 176 8.14.3.3.2 Meta-analysis of the...

Figure 1 Publications identified in Sci Finder including the searched term gabapentin

In addition, collective analysis of the SAR reported to date indicate several distinguishing features of this area, including the observation that very subtle changes to the carbon skeleton of amino acids that target this protein result in drastic changes to in vitro and in vivo properties and that the stereochemical disposition of functionality plays a profound role in the SAR. Examples pertaining to the above points as well as an overall overview of the SAR in this area are presented below....

Comprehensive Medicinal Chemistry II Volume 8 Case Histories

Taylor and David J. Triggle ISBN 0-08-044513-6 (set) 8.01 Introduction, Pages 1-5, W.T. Comer 8.02 Reflections on Medicinal Chemistry Since the 1950s, Pages 7-15, H. Timmerman 8.03 Medicinal Chemistry as a Scientific Discipline in Industry and Academia Personal Reflections, Pages 17-27, C.R. Ganellin 8.04 Some Aspects of Medicinal Chemistry at the Schering-Plough Research Institute, Pages 29-51, A.K. Ganguly 8.05 Viread, Pages 53-58, R. Oliyai and M. Fardis 8.06...

Discovery of Duloxetines Preclinical Effects on the Lower Urinary Tract

Duloxetine (Figure 2) was discovered by Robertson, Krushinski, and Wong, as part of a chemistry effort by Eli Lilly and Co. aimed at finding combined serotonin norepinephrine reuptake inhibitors (SNRIs) as treatments for depression.26 In the first series of experiments testing duloxetine's effects on lower urinary tract function,27 I chose to use the cat as the experimental species because most of the preceding experiments with 5HT and norepinephrine had been conducted in cat and thus provided...

C

Figure 3 Electromyographic (EMG) activity recorded from the rhabdosphincter (upper traces in panels a-c) and bladder pressure (lower traces in panels a-c) during infusion of saline into the bladder (a), during infusion of dilute acetic acid into the bladder to induce bladder irritation and bladder overactivity (b), and during continued infusion of acetic acid into the bladder following administration of duloxetine (c). (Adapted from Thor, K. B. Katofiasc, M. A. Pharmacol. Exp. Ther. 1995, 274,...

Ch2xch2ch2nhcnhch3

4 Cimetidine R CH3, X S, Y N-C N 8.03.2.2 Structure-Activity Analysis Having been trained as an organic chemist I had to learn medicinal chemistry 'on the job.' I realized that there was a major problem in communicating with other disciplines that arises from the language, and concepts, which we have been taught and then take for granted. The words we use with other scientists appear to be the same but our own appreciation of them depends upon the context in which they were presented to us. The...

Early Clinical Studies

Gabapentin was studied in animal toxicology at Goedecke from about 1980 to 1982, and was first studied for tolerance, safety, and pharmacokinetics in healthy human subjects in a study contracted from Goedecke in 1982.29 Clinical phase I single-dose and multiple-dose tolerance studies showed elimination with a plasma half-life of about 6 h and doseproportional absorption.29 Clinical phase II studies with gabapentin began in 1983 and continued in 1984 and 1985 with several quite small studies...

Cholecystokinin

My other highly productive collaboration was with Professor Jean-Charles Schwartz, Director of an Institut National de la Sante et de la Recherche M dicale (INSERM) Unit in Paris, France. I had previously had a strong collaboration with him on histamine research when I was at SK& F We were very lucky to share a large grant from the Upjohn Company (Kalamazoo, MI, US) for a proposal to discover an inhibitor of the peptidase that inactivates the octapeptide neurotransmitter, cholecystokinin-8...

Lower Urinary Tract Function and Dysfunction

The function of the lower urinary tract is to store and periodically release urine.1 The lower urinary tract is composed primarily of smooth muscle that forms a reservoir (the urinary bladder) and an outlet (the urethra), which has a 'valve' -the urethral rhabdosphincter - that is composed of striated muscle. Regulation and coordination of urine storage and release (i.e., micturition) is accomplished by a series of spinal and spinobulbospinal reflexes, respectively (Figure 1). These reflexes...

The Unique Action of Omeprazole

The success of omeprazole in the clinic could be ascribed to the very effective inhibition of gastric acid secretion achieved through specific inhibition of the gastric H+ ,K+-ATPase, which constitutes the gastric acid (or proton) pump. In whole-body autoradiography in mice, using 14C-labeled omeprazole, the radiolabel was confined to the gastric mucosa, and further studies showed that omeprazole only binds to the H + ,K+-ATPase in the gastric mucosa. The elucidation of the mechanism of action...

Och3

Figure 3 In vitro and in vivo activity of first azetidinones. ACAT( 25 M) 83 Inh. IC50 7.5 M Hamster (100 mg kg-1) SC -10 CE -26 in vivo activity of compounds. Based on this observation, Burnett et al. opted to disregard the ACAT activity of subsequent analogs and focus on optimizing the in vivo activity of compounds, guided solely by activity in the cholesterol-fed hamster. The absence of an in vitro assay clearly made this an extraordinarily challenging medicinal chemistry effort....

Drug Induced Changes in Calcium Channel Function

Building upon previous findings, David Dooley and colleagues (Pfizer Ann Arbor) showed that gabapentin reduces calcium influx and neurotransmitter release from rat and human brain tissues.72-78 Alexander McKnight and YP Maneuf (Parke-Davis Cambridge) found that gabapentin reduced glutamate release in a manner suggesting relevance for analgesia.79,80 Electrophysiologists in Cambridge and at Aberdeen University in the UK demonstrated changes in calcium channel and synaptic function that were...

Early Clinical Trials

In view of the putative resemblance between EAE and MS8 and based on the efficacy demonstrated by GA in suppressing EAE in all species including primates, both rhesus monkeys and baboons, the next step was testing it in MS patients. We first conducted some basic toxicological studies in our laboratory which included acute and subchronic administration to mice, rats, rabbits, and beagle dogs, uptake studies and Ames test (mutagenicity test). GA was found to be nontoxic and eligible for phase I...

Me

U-97456 realized another important SAR finding. When the optimal N-hydroxyacetyl substituent found on U-97456 was incorporated into the piperazinyl fluorophenyl oxazolidinone (giving eperezolid), it also engendered very high potency, and excellent oral in vivo efficacy comparable to vancomycin subcutaneously (s.c.), as well as an excellent 30 day toleration profile. This same moiety has subsequently been singled out by other researchers as bringing about optimal activity in additional...

Biographies

Gideon A Rodan received his MD and PhD degrees from the Hebrew University and the Weizman Institute of Science, respectively. He was professor and head of the Department of Oral Biology at the University of Connecticut, moving to Merck & Co. in 1985 where he established the Department of Bone Biology and Osteoporosis Research. His scientific contributions include establishing transformed osteoblastic cell lines, regulation of bone cell metabolism by hormones and cytokines, mediation of...

From Animal Pharmacology to a Human Therapeutic

Following the discovery of the stimulant effects of adrafinil in rodents, it was essential to select a viable therapeutic indication consistent with the effects observed. At that time, Lafon had a research and development agreement with a large pharmaceutical company that wanted to focus clinical studies and indications in 'psychogeriatrics.' That led to a new drug application being filed only in France with an approval for 'vigilance and mood disorders in the elderly.' At the same time Louis...

Scheme 1 Mechanism for the transformation of omeprazole in acid Formation of the active sulfenamide or alternatively

Elucidation of the mechanism of action of omeprazole, Arne Br ndstr m, Bj rn Wallmark, and I were jointly awarded the Wilhelm Westrups Prize in Lund, Sweden, in 1993. We filed a patent application on the sulfenamides in June 1984. Dramatically, at a medicinal chemistry symposium in Cambridge, UK, in September 1985, Bjorn Wallmark and I gave a joint oral presentation on the omeprazole mechanism16'17 and, at the following poster session, Byk Gulden and SmithKline Beecham presented a poster with...

G1 Introduction

W T Comer, TorreyPines Therapeutics, Inc., La Jolla, CA, USA 2007 Elsevier Ltd. All Rights Reserved. 8.G1.2 Case 1 8.G1.3 Case 2 8.G1.4 Case 3 8.G1.5 Case 4 References The role of a medicinal chemist in drug discovery is the design, synthesis, and registration of the best compound for treating a particular disease condition. The job is not finished when the most potent compound for a given target (receptor, ion channel, enzyme) is identified. The best compound of the series for bioavailability...

Rigid Analogs

Some follow-up studies focused on defining the active conformation of azetidinone CAIs, with the dual purpose of improving the potency of compounds as well as providing additional tools to understand the nature of the molecular target. That the conformation of the sidechain tether was important for activity was first suggested by the difference in activity of the E- and Z-propenyl derivatives 54 and 55 (Figure 13).13 Additionally, the fact that potent compounds CE -47 at 50 mg kg-1 Figure 12...

Pharmacokinetics

The P-C-P backbone of ALN endows it and the entire BP class with several common properties, especially regarding pharmacokinetics. The highly charged phosphonate moieties of ALN limit absorption in the gut to around 0.6 , when administered fasting and formulated as the trihydrate monosodium salt of alendronic acid, with similar values seen for other N-BPs. Entry into the bloodstream is by paracellular transport, and renal excretion is the only route for elimination in part by glomerular...

Omeprazole Prodrug for Parenteral

In the mid-1980s a special project was devoted to the development of a prodrug of omeprazole (itself being a prodrug) for parenteral administration, both intravenously and intramuscularly. The challenge was to make the compound much more water-soluble (the entire dose for humans soluble in 1-2 mL), while ensuring its chemical stability. We established a close collaboration with one of the best-known scientists in the prodrug area, the late professor Hans Bundgaard of the Farmaceutiske Hojskole...

The Discovery of Ritonavir Norvir

A significant improvement on the rapid clearance of A-80987 was achieved in subsequent SAR studies. In vitro metabolism studies in human liver microsomes indicated that N-oxidation of the pyridyl groups of both A-77003 and A-80987 occurred rapidly to produce the major metabolites. Systematic studies in which each of the two pyridyl groups were independently replaced with thiazolyl groups, which were more stable to oxidation, suggested that further improvements in the pharmacokinetics of A-80987...

Historical Overview

Carvedilol (Coreg) is commonly referred to as a third-generation beta adrenoceptor blocker (beta blocker) with vasodilatory and antioxidant properties. These varied activities are attributed to different parts of the carvedilol molecule (Figure 1). Carvedilol was originally discovered in the early 1980s as a novel beta blocker for the primary therapeutic indications of angina and hypertension, which were traditional uses of drugs of this class at the time. However, the true novelty behind...

In Search and Discovery of Potential New Therapeutic Indications Conclusions

The search for additional indications for modafinil was directed toward diseases associated with wake deficit and somnolence but also to those in which symptoms could be related to cognition deficits, with modafinil showing human efficacy in attention deficit hyperactivity disorder (ADHD). Preclinical studies also showed a beneficial effect of modafinil in models of depression. Since its discovery, modafinil has proven to be an efficient and safe therapeutic agent. Many biochemical and...

Key Structure Activity Relationship Refinements

Following the establishment of the Oxazolidinone Working Group, over the next two and a half years (leading up to the discovery of linezolid), the team identified a number of proprietary and safe oxazolidinone series. The Hutchinson laboratory initially focused on examining the effect of an additional methyl substitution at C-5, or on the C-5-acetamidomethyl side chain itself in the indanyl oxazolidinone template,21 but both resulted in complete loss of activity.25 This laboratory then...

Potassium Ion Channels

At UCL, Professor DH Jenkinson in the Pharmacology Department had strong interests in calcium-activated potassium ion channels. We were fortunate to obtain a 5-year grant from the Wellcome Trust to fund both medicinal chemistry and pharmacology (electrophysiology). In chemistry this provided the seed that we were able to grow by accommodating project students and academic visitors over many years. The small-conductance Ca2 + -activated K+ channel (SKca) is found in many cell types and was...

Ezetimibe

J W Clader, Schering-Plough Research Institute, Kenilworth, NJ, USA 2007 Elsevier Ltd. All Rights Reserved. 8.07.2 Discovery of the Prototype Azetidinone Cholesterol Absorption 8.07.3 Defining the Nature of the Target 8.07.3.1 Structure-Activity Relationship on the Azetidinone Nucleus 8.07.4 The Discovery of Ezetimibe 8.07.8 Mechanism of Action Studies Atherosclerotic coronary artery disease remains a major cause of death and morbidity worldwide and a significant drain on healthcare resources,...

H

8.17.1.2 My First Pharmaceutical Project In 1974, B rje Wickberg and I, along with Professor Arvid Carlsson (Nobel Laureate in Medicine in 2000) of the Department of Pharmacology, University of G teborg, established an industrial collaboration, supported by the Swedish Board for Technical Development (STU) and sponsored by the Swedish pharmaceutical companies Astra and Kabi, with the aim of developing a new alcoholic deterrent with fewer side effects than disulfiram (Antabuse, the alcoholic...

The Japanese Trial

This trial34 was the first to show efficacy in neurogenic bladder (and is the only trial published for any overactive bladder condition to date). This important trial also supported the early positive results for duloxetine in SUI. This study showed a reduction from 1.7 to 0.3 incontinence episodes per day in neurogenic bladder patients at 20 mg (but no effect at 10 mg) and a reduction from 3 to 1 incontinence episodes day at both 10 and 20 mg doses in SUI patients. Although the trial was a...

The First Trial SAAA

The initial clinical trial33 examined stress, mixed, and urge incontinent patients because of duloxetine's affects on both the rhabdosphincter and bladder capacity. This preliminary proof-of-concept trial for duloxetine's use in treating incontinence was at a dose of 20 mg q.d., which is substantially lower than that used in later trials (i.e., 40-60 mg b.i.d.). In hindsight, based on the low dose of duloxetine, the small number of SUI patients (22 on duloxetine, 11 on placebo), and the extreme...

Challenges in Bringing Forward the First Therapeutic Treatment for Incontinence

In the early 1990s, therapy for stress urinary incontinence relied on pelvic floor exercises and surgery. Bringing the first drug forward to treat any indication provided a number of challenges, such as extent of medical need and clinical trial design. Unique to duloxetine's trials in incontinence were (1) the fact that urologic thought leaders' prevailing opinion at that time was that stress incontinence was 'an anatomical defect' that would be only amenable to surgery and not pharmacological...

Selection of yAmino Butyric Acid as a Mimetic Compound to Target GABAb Receptors

In early 1973, Gerhardt Satzinger of Goedecke conceived a series of about 25 derivatives of GABA that were later synthesized. This project was an attempt to design GABA mimetic drugs acting at GABA receptors that (unlike GABA) would penetrate the blood-brain barrier. At this early time, GABA was only recently acknowledged as an inhibitory neurotransmitter, and there were only a few known GABA agonists, of which baclofen (a selective GABAb agonist) was one example.1 Most of the compounds that...

Subsequent Trials in Stress Incontinence

The results from the next trial and all subsequent trials have been or will be published as full-length papers in peer-reviewed journals.39-42 Briefly, subsequent trials in North America, South America, Europe, Africa, and Australia have continued to show dose-dependent improvements in patients with SUI. The top dose studied and being prescribed in those countries where it has launched is 40 mg b.i.d. Surprisingly (to me at least), duloxetine is just as effective in severe SUI patients as it is...

Innovation

The risk is that the current decline in productivity in the big pharma industry is putting more and more pressure on effectivity, with research dominated by targets for delivery of numbers of synthesized compounds, CDs, and patent applications at predestined deadlines. Although high productivity in the laboratory is important, such benchmarking may be at the expense of new thinking and innovation. I believe that organization of drug discovery work according to time-lines (e.g., hit...

Medicinal Chemistry as a Scientific Discipline in Industry and Academia Personal Reflections

C R Ganellin, University College London, London, UK 2007 Elsevier Ltd. All Rights Reserved. 8.03.2 SmithKline & French Laboratories 18 8.03.2.2 Structure-Activity Analysis 19 8.03.2.3 Dynamic Structure-Activity Analysis 19 8.03.2.4 University Collaborations 20 8.03.2.5 Diamino-Nitroethene as a Bioisostere 20 8.03.2.6 Medicinal Chemistry Summer School 21 8.03.2.7 Research Post-Cimetidine 21 8.03.3 University College London 23 8.03.3.1 University College London Medicinal Chemistry 23 8.03.3.2...

Lessons from the Ritonavir Development Program

Several key findings from the development and clinical programs with ritonavir had a major impact on the subsequent HIV protease inhibitor discovery effort, leading ultimately to the discovery of lopinavir. The first was the characterization of drug resistance during ritonavir monotherapy in phase II studies. Longitudinal assessment of plasma samples from patients who initially responded to therapy with a drop in viral load, but whose plasma HIV RNA rebounded over time, revealed the stepwise...

S

AUC (p.o.) 4.8 xg hml-1 f1 2 (i.v.) 1.0 h Bioavailability 48 Figure 11 Properties of analogs of SCH 44342 with an sp3 center at C-11 (AUC, area under the plasma concentration-time curve). AUC (p.o.) 9.2 ig hml-1 f1 2 (i.v.) 1.8 h Bioavailability 54 enantiomer, except that the tricyclic ring is rotated 180 relative to the active site. The increased potency of the 3-bromo analogs was due to the additional interactions with the aromatic amino acids, as mentioned above. A summary of the...

The Medical Need for New Antibiotics Multi Drug Resistance

As a consequence of the selective pressure of antibiotic therapy on bacterial populations, the evolution of bacterial resistance to antibiotics is an expected and natural phenomenon.7 Resistance results from survival and multiplication of those bacteria having a mutation or acquired resistance determinant that allows those organisms to remain viable in the presence of the antibiotic. The problem of cross-resistance presents a formidable hurdle that complicates the difficult objective of...

Figure 1 Structures of pyrophosphate a basic bisphosphonate and alendronate Note that in the basic structure

Hydrophilic phosphonate moieties limit the penetration of BP molecules through cellular lipid bilayer membranes to undetectable levels, so that distribution is limited to an extracellular compartment and, one day after a dose, is essentially limited to the surface of bone. The bioavailable ALN is thus rapidly cleared from the circulation with an end result of about 50 binding to the hydroxyapatite bone mineral and the remainder being excreted in the urine.21 This half-life in the circulation is...

The Discovery and Structure Activity Relationship SAR of Gabapentin Serendipity Leads to the Discovery of a New Drug

As it is sometimes the case in drug discovery, the discovery of gabapentin was made through a rather indirect path. Since GABA does not penetrate the blood-brain barrier, Satzinger and colleagues directed attention to increasing the oral bioavailability of GABA, by raising the log P of its analogs through the incorporation of lipophilic groups on the carbon backbone.1-3 Although compounds described in Satzinger's original work did possess anticonvulsant activity (as did centrally administered...

Elsevier Ltd All Rights Reserved

8.16.1.1 Osteoporosis and Fracture Risk 199 8.16.1.2 Clinical Use of Alendronate (Fosamax) 200 8.16.2 Bisphosphonate Properties 200 8.16.3 Mechanism of Action 202 8.16.3.1 Alendronate Action at the Molecular Level 202 8.16.3.2 Nitrogen-Containing Bisphosphonate Inhibition of the Cholesterol 8.16.3.3 Farnesyl Diphosphate Synthase as the Molecular Target of Alendronate 202 8.16.3.4 Inhibition of Farnesyl Diphosphate Synthase Blocks Protein Isoprenylation 8.16.3.5 Evidence for Molecular Mechanisms...

Summary

Based on all the above observations lonafarnib was recommended for clinical studies, and presently it is in third phase of the trial in cancer patients. 1. Clader, J. W J. Med. Chem. 2004, 47, 1-9. 2. Sliskovic, D. R. Picard, J. A. Krause, B. R. Prog. Med. Chem. 2002, 3, 121-171. 3. Schnitzer-Polokoff, R. Compton, D. Boykow, G. Davis, H. Burrier, R. Comp. Biochem. Physiol. 1991, 99, 665-670. 4. Burnett, D. A. Caplen, M. A. Davis, H. R., Jr. Burrier, R. E. Clader, J. W J. Med. Chem. 1994, 37,...

Figure 5 Responder analysis of 20 mg qd duloxetine DUL versus placebo PL as defined by a 70 improvement from baseline

Figure 6 Effects of placebo (P) and duloxetine (D) at 20, 30, 40 mg q.d. on stress-pad test (SPT), incontinence episode frequency (IEF), 24-h pad weight (24PT), and incontinence quality of life (IQOL) in SUI patients. (Adapted from Zinner, N. Sarshik, S. Yalcin, I. Faries, D. DeBrota, D. Riedl, P. Thor, K.B. Efficacy and Safety of Duloxetine in Stress Urinary Incontinent Patients Double-Blind, Placebo-Controlled Multiple Dose Study. International Continence Society, 28th Annual Meeting,...

Bazedoxifene

Bazedoxifene (TSE-424 Figure 10) is a novel SERM developed by Wyeth Pharmaceuticals that is currently in phase III clinical trials for the prevention and treatment of postmenopausal osteoporosis. It is an indole-based estrogen receptor ligand that has been stringently selected to ensure an improved profile over its predecessor raloxifene. It was developed using preclinical selection parameters, which included favorable effects on the skeleton and lipid metabolism, demonstrable mammary and...

Beta Amino Acids

Evidence that activity at both the system L transporter and also at the a2-S protein was needed for in vivo activity was again provided by a series of cyclopropyl-based a-substituted -amino acids reported by the Pfizer group in 2005.27 This disclosure was notable in being the first report of the SAR of -amino acids with affinity for a2-S (Table 14). In this study, several potent ligands for the a2-S protein were found, but none were substrates of the system L transporter, as measured by...

In Search and Discovery of Potential New Therapeutic Indications

The search for additional indications for modafinil naturally focused on diseases associated with wake deficits and somnolence. The effects of the drug in an animal model of sleep-disordered breathing suggested that modafinil might be effective in reducing sleepiness associated with sleep apnea,50 and this was subsequently demonstrated in the clinic.51-53 Other disorders where somnolence or sedation was concomitant with the disease, e.g., Parkinson's disease,54-56 myotonic dystrophy,57-60...

Design of Symmetry Based Human Immunodeficiency Virus Protease Inhibitors

The discovery of HIV protease inhibitors began with one of the first applications of modern genomics in medicine. Shortly after the isolation and identification of HIV as the causative agent for AIDS, its entire retroviral genome was sequenced and homology modeling2 revealed a genetic motif (Asp-Thr-Gly) suggestive of an aspartic proteinase (HIV protease). HIV encodes its structural and enzymatic proteins in the gag and pol genes, respectively, and translation provides large gag and gag-pol...

Nitrogen Containing Bisphosphonate Inhibition of the Cholesterol Biosynthetic Pathway

Over 15 years ago, it was shown that certain BP derivatives (isoprenoid (phosphinylmethyl) phosphonates) weakly inhibit the cholesterol biosynthetic enzyme squalene synthase.51 The search for more potent inhibitors that might block cholesterol production revealed that the N-BPs incadronate (YM175) and ibandronate potently inhibit squalene synthase.52 Subsequent studies examined the structure-activity relationship (SAR) for inhibition of squalene synthase.53-55 In vivo testing showed that...

Structure

Bisphosphonates (BPs) are analogs of pyrophosphate (P-O P) in which the geminal oxygen has been substituted by carbon (Figure 1). No known enzyme can cleave the P-C-P bond, which minimizes the possibility for metabolism, and none has been detected for ALN in pharmacokinetic studies.34'35 A main feature of the P-C-P backbone is that, by adhering to the hydroxyapatite component of bone, it localizes these compounds in the target tissue. While the affinity for human bone is low (KD in the 60-120...

The Food and Drug Administration The Last Major Obstacle

The story of the development of carvedilol in heart failure did not immediately have a happy ending based on the clinical results described above. The drug still needed approval by the FDA before it could be used widely in patients with congestive heart failure. Based on the striking results from clinical trials, and the known deadly outcome of this disease, our anticipation was that the FDA would readily (and rapidly) approve carvedilol for use in heart failure. However, we were in for an...

Carbazol antioxidant

Over the next decade, compelling data were generated in a variety of in vitro and in vivo experimental systems that highlighted novel and unusually effective cardioprotective properties of the drug that resulted in part from the beneficial hemodynamic effects emanating from beta blockade and alpha blockade, and in part from the unique antioxidant, antiapoptotic, and antiproliferative properties of the molecule. Based on these extensive studies, the highest levels of corporate and R& D...

Figure 3 Mechanism of action of glatiramer acetate GA Copaxone Copolymer 1 in EAE and MS

GA is thought to act by inducing a population of regulatory (Th2-type) T cells that migrate to inflammatory sites in the CNS, where they are activated by cross-reacting myelin antigens to exert their beneficial bystander effect. In addition to bystander suppression, GA may also confer neuroprotection, as indicated by both animal and human studies. The latter activity may be of relevance for both MS and for neurodegenerative diseases. Furthermore, in accord with its capacity to induce Th1 to Th2...

Incontinence Markets

Without any historical pharmaceutical sales data for an indication, the market potential is difficult to predict because most financial models are based on sales of competitors' products. Since there were no well-marketed products for stress urinary incontinence, it was difficult to develop a financial model. In 1992, even sales of urge incontinence products were remarkably small for example, the top UUI medicine was Ditropan, which only had 92 million days of therapy prescribed in the USA, and...

Inhibition of Farnesyl Diphosphate Synthase Blocks Protein Isoprenylation and Sterol Synthesis

FPP synthase is responsible for the production of isoprenoid lipids FPP (15 carbon) and geranylgeranyl diphosphate (GGPP) (20 carbon). While FPP, formed by the condensation of three isopentenyl diphosphates (or isomers), is primarily used to synthesize cholesterol, it also can be used for protein isoprenylation. FPP can also be condensed with a fourth isopentenyl diphosphate to form GGPP. The blockade in synthesis of GGPP, albeit through indirect effects on FPP synthase, is critical for N-BP...

Clinical Trials of Carvedilol in Heart Failure The Bottom Line

The decision having been taken to launch clinical trials with carvedilol in heart failure was a relief, as well as a concern what if the drug did not work, or worse, what if it hurt people with heart failure as the textbooks at the time, and conventional wisdom, indicated it would Because of these concerns, clinical trials progressed slowly at first through phase I and phase II. Notably, in the phase II clinical trials, some of the hoped- for benefits seemed to be occurring. In a small, but...

Hepsera

R Oliyai and M Fardis, Gilead Sciences Inc., Foster City, CA, USA 2007 Elsevier Ltd. All Rights Reserved. 8.06.2 Synthesis and Formulation 60 8.06.3 Mechanism and Site of Bioconversion 61 8.06.5 Conclusion 62 References 62 According to the World Health Organization, approximately 2 billion people have been infected with hepatitis B and over 350 million have chronic hepatitis B infection.1 Over 1 million patients have been diagnosed with hepatitis B in the US and Europe.2 Only 15 of the infected...

Synthesis

A number of syntheses of ezetimibe and related compounds have been reported, several of which were utilized in the course of these investigations.31-38 Many of these are based on an Evans-type oxazolidinone condensation to establish the correct stereochemistry on the azetidinone ring. Figure 22 shows a representative synthesis of ezetimibe. In addition to the use of the oxazolidinone, this synthesis also features a Corey oxazaborolidine reduction to set the (S) stereochemistry of the side chain...

Viread

R Oliyai and M Fardis, Gilead Sciences Inc., Foster City, CA, USA 2007 Elsevier Ltd. All Rights Reserved. 8.05.2 Pharmacokinetics of Tenofovir Disoproxil Fumarate 54 8.05.3 Synthesis and Formulation 55 8.05.4 Mechanism and Site of Bioconversion 55 8.05.6 Conclusion 56 References 56 According to estimates from the United Nations acquired immunodeficiency syndrome (UNAIDS) World Health Organization (WHO) AIDS Epidemic Update (December 2004), 37.2 million adults and 2.2 million children were...

The Identification of Eperezolid U100592 and Mechanism of Action Studies

In late 1992, our team decided to focus all of our SAR exploration efforts on only one of the three most interesting lead oxazolidinones series (i.e., 5'-indolines, piperazines, and tropones), in order to maximize our probability of success in identifying a drug candidate. After assessing the overall attributes and issues associated with each of the three series, the team decided to focus on the piperazinyl oxazolidinone series. While difluoro substitution in the troponyl and piperazinyl series...

Raloxifene Structural Characteristics

Recent progress in our understanding of the molecular biology of estrogen receptor action has provided a great deal of evidence which promises to increase our understanding of the mechanism through which SERMs elicit their tissue-specific effects. This in turn has enhanced interest in raloxifene and increased the interest in developing new tissue-specific SERMs. The identification of numerous coactivators and corepressors150,151 which modulate receptor function and the realization that there...

Conclusions

In the 30 or so years since the initial discovery of its stimulant effect in mice, despite an impressive amount of preclinical, pharmacoclinical, and clinical studies, modafinil has yet to reveal all the secrets of either its mechanism of action or its potential for new therapeutic applications. The fascinating unique profile of this drug (awarded the French Science and Defense Prize in 1994 and the Galien Prize in 1997) is still in search of a mechanism103 that could help to explain its...

Mechanism of Action Studies

Clearly one of the important goals in this area has been identification and characterization of the molecular target of these compounds and the establishment of an in vitro assay. Considerable progress has been made in this area since the discovery of ezetimibe, with the primary focus being on Niemann-Pick C1 Like 1 Protein (NPC1L1). Altman, Davis et al. have shown that NPC1L1 is critical for the uptake of cholesterol by intestinal enterocytes and is a key modulator of whole-body cholesterol...

GP GH Lopinavir ABT378

Figure 2 Structures of symmetry-based HIV protease inhibitors A-74704, A-77003, A-80987, ritonavir (ABT-538), and lopinavir (ABT-378). Figure 3 Binding of diastereomeric diols in the HIV protease active site. (a) Overlap of the central portions of S,S-diol (A-76928, green) and R,R-diol (A-76889, magenta). Hydroxyl groups (red) are projected down toward the catalytic aspartates. (b) Overlap of the above inhibitors with the R,S-diol (A-77003, blue), showing the shift from symmetry to allow the...

Duloxetine Duloxetine Placebo Placebo baseline endpoint baseline endpoint

Figure 4 Line graph 'baseline to endpoint' for (a) stress-pad test (SPT) and (b) incontinence episode frequency (IEF). Each line connects an individual SUI patient's baseline and endpoint values. Duloxetine significantly decreased amount of SPT leakage (p 0.02 versus placebo, ANCOVA on ranked changes with baseline values as covariate) and frequency of incontinence, but it was not statistically significant (p 0.34 versus placebo, ANCOVA on ranked changes with baseline values as covariate)....

Clinical Trial Considerations

Being the first to initiate regulatory submission quality clinical trials in a therapeutic indication also carries substantial challenges 1. There are no physicians with regulatory submission clinical trial experience specific to your indication. 2. There are no publications indicating O which efficacy measures are best O inclusion exclusion criteria O recruitment rates O trial duration or design O anticipated placebo response rates or intrinsic variability to allow power calculations O quality...

Esomeprazole The FollowUp

Although omeprazole provided more effective control of acid secretion than previous therapies, it was not equally effective in all patients. Our next goal was therefore to find a compound with improved pharmacokinetic and metabolic properties that exhibited increased bioavailability, and reduced the interindividual variation in effectiveness observed for omeprazole. A focused research program began in 1987 to find new protein pump inhibitors (PPI) that fulfilled these requirements. After...