The Design of Ezetimibe

Based on the activity of 9, the phenols 10, 11, 12, 13, 14, and 15 were synthesized, and their in vivo activities determined. The results are summarized in Figure 4.

Based on the structure-activity relationship as described in Figure 2 and also on the biological activities of the possible metabolites as described in Figure 4, several new analogs were synthesized. Ezetimibe was found to be the most potent among all the analogs synthesized in inhibiting the absorption of cholesterol. The structure of ezetimibe8 and a summary of its design is presented in Figure 5.

Hamster (50 mg kg-1) Cholesterol ester -68%

Hamster

Cholesterol ester ED50: 0.89 mg kg-1

Figure 4 In vivo activities (in the hamster) of phenols 10-15. (Reprinted with permission from Clader, J. W. J. Med. Chem. 2004, 47, 7. Copyright (2004) American Chemical Society.)

Figure 5 Structure-activity relationship of ezetimibe. (Reprinted with permission from Clader, J. W. J. Med. Chem. 2004, 47, 7. Copyright (2004) American Chemical Society.)

Blocked metabolism

Figure 5 Structure-activity relationship of ezetimibe. (Reprinted with permission from Clader, J. W. J. Med. Chem. 2004, 47, 7. Copyright (2004) American Chemical Society.)

8.04.2.5 The Synthesis of Ezetimibe9

The keto acid 16 was converted to 17, and then reduced to 18 using Corey's oxazaborolidine catalyst (Scheme 2). The titanium enolate of the silylated derivative of 18 was condensed with the silylated phenolic Schiff base 19, to yield 20. The basic nitrogen atom of 20 was silylated in situ, and then treated with tetrabutyl ammonium fluoride, to form the azetidinone ring. Final deprotection of the silyl groups with acid yielded ezetimibe.

8.04.2.6 The Biological Activity of Ezetimibe

The cholesterol absorption inhibitory property of ezetimibe was compared with SCH 48461, and the results are summarized in Table 2. In every species studied, ezetimibe showed dramatic improvement in activity when compared with SCH 48461, and, in monkeys, ezetimibe showed the greatest activity.

Scheme 2 Reprinted with permission from Clader, J. W. J. Med. Chem. 2004, 47, 8. Copyright (2004) American Chemical Society.

Table 2 Cholesterol absorption inhibition of ezetimibe and SCH 48461a

Species

EDS0 (mgkg 1)

SCH 48461

Ezetimibe

Hamster

2.2

0.04

Rat

2.0

0.03

Monkey

0.2

0.0005

Dog

0.1

0.007

Reprinted with permission from Clader, J. W. J. Med. Chem. 2004, 47, 7. Copyright (2004) American Chemical Society. a Blood levels significantly lower for ezetimibe.

In parallel, we studied the synergistic effect of ezetimibe, along with a statin for lowering cholesterol levels. Thus, ezetimibe (0.007 mgkg_ ^ and lovastatin (5mgkg_ ^ were administered orally to two different sets of chow-fed dogs for 14 days. Neither ezetimibe nor lovastatin showed significant activity; however, the combination showed a dramatic reduction in serum cholesterol levels (Figure 6). Based on all these results, ezetimibe has progressed to the clinic as a monotherapy agent and also in combination with simvastatin. The combination drug, named Vytorin, was jointly developed by Schering-Plough and Merck.

8.04.2.7 The Results of Clinical Trials of Ezetimibe

Based on all these observations, ezetimibe was advanced alone and also in combination with simvastatin and atorvastatin in the clinic, and the results are presented in Figure 7. In the clinic,10-13 ezetimibe (10 mg) when administered alone reduced serum cholesterol levels by 18.5%, on average, and in combination with simvastatin (10 mg), serum cholesterol levels were reduced by 51.9%.

Based on safety studies and clinical response, ezetimibe has been approved for human use as a monotherapy, and Vytorin (ezetimibe plus simvastatin) has also been approved by the FDA for reducing serum cholesterol levels.

8.04.2.7.1 The mechanism of action of ezetimibe

Scientists at the SPRI have recently discovered that ezetimibe blocks the activity of the cholesterol transporter NPC1L1 that is expressed at the apical surface of enterocytes.14 It is believed to be the transporter for dietary cholesterol absorption. As a further proof, it was demonstrated that in NPC1L1 knockout animals, ezetimibe was ineffective in preventing the absorption of cholesterol.

"D

40 n

15 0H

Ezetimibe, 0.007 mg kg-1 (n=5) Lovastatin, 5 mg kg-1 (n=5) Combination (n=5)

Treatment (days)

Figure 6 Effects of ezetimibe and lovastatin on cholesterol levels. (Reprinted with permission from Clader, J. W. J. Med. Chem. 2004, 47, 7. Copyright (2004) American Chemical Society.)

SIM 10 mg SIM 20 mg ATO 10 mg

Placebo EZE 10 mg SIM 10 mg + EZE 10 mg SIM 20 mg + EZE 20 mg ATO 10 mg + EZE 10 mg

51.9

51.9

12.5

Figure 7 Results from a clinical trial of ezetimibe (EZE) alone and in combination with simvastatin (SIM) and atorvastatin (ATO) on cholesterol levels. (Reprinted with permission from Clader, J. W. J. Med. Chem. 2004, 47, 8. Copyright (2004) American Chemical Society.)

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