Design, Synthesis, and X-ray Crystallographic Analysis of a Novel Class of HIV-1 Protease Inhibitors

• Published in: Journal of medicinal chemistry Vol. 54; no. 20; pp. 7176 - 7183
• Main Authors: Ganguly, Ashit K, Alluri, Sesha S, Caroccia, Danielle, Biswas, Dipshikha, Wang, Chih-Hung, Kang, Eunhee, Zhang, Yong, McPhail, Andrew T, Carroll, Steven S, Burlein, Christine, Munshi, Vandna, Orth, Peter, Strickland, Corey
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 27.10.2011; Amer Chemical Soc
• Subjects: Carbamates - chemical synthesis; Carbamates - chemistry; Chemistry, Medicinal; Crystallography, X-Ray; Drug Design; HIV Protease - chemistry; HIV Protease Inhibitors - chemical synthesis; HIV Protease Inhibitors - chemistry; Life Sciences & Biomedicine; Models, Molecular; Molecular Structure; Pharmacology & Pharmacy; Protein Binding; Protein Conformation; Science & Technology; Stereoisomerism; Structure-Activity Relationship; Thiazepines - chemical synthesis; Thiazepines - chemistry; TMC114; POTENT; GENERATION; DISCOVERY
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm200778q

In the present paper, design, synthesis, X-ray crystallographic analysis, and HIV-1 protease inhibitory activities of a novel class of compounds are disclosed. Compounds 28–30, 32, 35, and 40 were synthesized and found to be inhibitors of the HIV-1 protease. The crucial step in their synthesis involved an unusual endo radical cyclization process. Absolute stereochemistry of the three asymmetric centers in the above compounds have been established to be (4S,2′R,3′S) for optimal potency. X-ray crystallographic analysis has been used to determine the binding mode of the inhibitors to the HIV-1 protease.