O

Figure 1 Structure of tenofovir disoproxil, tenofovir, and the bioconversion pathway. readily undergo passive diffusion across cellular membranes and intestinal mucosa, resulting in low bioavailability after oral administration.6'7 A series of novel prodrugs of tenofovir was designed to overcome the pharmacokinetic limitations of tenofovir.8'9 These prodrugs were engineered to mask the polar phosphonic acid functionality using a novel oxycarbonyloxymethyl linker to allow for passive diffusion...

Development of Gabapentin for Epilepsy

The first clinical study of gabapentin in epilepsy showing efficacy was conducted with 25 patients in 1985 as a placebo-controlled add-on crossover study in refractory partial seizures (Bernd Schmidt et al., Goedecke, unpublished data), unpublished data. All patients were maintained on their prior medications, but were then crossed over between four different study groups with the addition of placebo, 300, 600, or 900 mg gabapentin per day. The 900 mg dose group showed a significant difference...

References

Living Agents of Disease GP Putnam's Sons New York, 1952. 2. Barber, M. Garrod, L. P Antibiotic and Chemotherapy Williams and Wilkins Baltimore, MD, 1963. 3. Franklin, T J. Snow, G. A. Biochemistry of Antimicrobial Action Academic Press New York, 1971. 4. Lesher, G. Y Froelich, E. J. Gruett, M. D. Bailey, J. H. Brundage, R. P J. Med. Pharm. Chem. 1962, 5, 1063-1068. 5. Walsh, C. Wright, G. Chem. Rev. 2005, 105, 391-393. 6. Alder, J. D. Drugs Today 2005, 41, 81-90. 7....

Figure 5 ac PKPD model for resistance development for HIV protease inhibitors d idealized PKPD profile with high

Sufficient resistance to overcome all drug concentrations encountered in a dosing cycle are produced, the drug loses its antiviral effect, and viral load rebounds to pretherapy levels (Figure 5a-c). This PK PD resistance model suggested that resistance could be delayed or prevented if (a) the drug was substantially more potent (i.e., much lower EC50), and or (b) the drug maintained higher plasma concentrations (particularly trough concentrations Figure 5d). Both of these goals were realized...

Raloxifene and Breast Cancer Prevention

The rationale for the use of SERMs, including raloxifene, as breast cancer preventives is based on a strategic hypothesis formulated when SERM action was first recognized in the late 1980s. The evidence to support the use of raloxifene in this paradigm stems from observations made in the laboratory91,96 and the clinic165 along with close monitoring of ongoing osteoporosis placebo-controlled trials. Previous studies have shown that raloxifene inhibits the growth of dimethylbenzanthracene-induced...

Some Aspects of Medicinal Chemistry at the Schering Plough Research Institute

A K Ganguly, Stevens Institute of Technology, Hoboken, NJ, USA 2007 Elsevier Ltd. All Rights Reserved. 8.04.2 The Discovery of Ezetimibe 30 8.04.2.1 The Synthesis and Biological Activities of Initial Leads 31 8.04.2.2 The Discovery of SCH 48461 31 8.04.2.3 The In Vivo Activity of SCH 48461 32 8.04.2.4 The Design of Ezetimibe 33 8.04.2.5 The Synthesis of Ezetimibe 34 8.04.2.6 The Biological Activity of Ezetimibe 34 8.04.2.7 The Results of Clinical Trials of Ezetimibe 35 8.04.2.7.1 The mechanism...

Demonstration of a Structure Toxicity Relationship A Strategy for Lead Progression

Fairly early on in our exploratory project we had identified one particularly interesting compound that demonstrated very good in vitro potency and oral in vivo efficacy comparable to DuP-721, and was found to have similar PK properties in the rat. This was the indanone oxazolidinone ( + )-U-82965 (5, PNU-82965),24,25 one of two cyclic ketones we had targeted in order to explore the consequence of restricting the rotational conformers of the DuP-721 methyl ketone, via constraint in a five- or...

The Discovery of Lopinavir and the Development of Kaletra Lopinavir Ritonavir

As mentioned previously, the evaluation of the antiviral potency of new protease inhibitors in the discovery program was expanded to include assays in the presence of 50 human serum, to best estimate 'in vivo potency.' Following the observation of substantial boosting by ritonavir, the preclinical pharmacokinetic screening protocol was also modified to include evaluation in rats and dogs, both alone and following codosing with ritonavir. The goal for an advanced generation protease inhibitor...