Journal of Medicinal Chemistry 1992-05-15

Synthesis and antiviral activity of a series of HIV-1 protease inhibitors with functionality tethered to the P1 or P1' phenyl substituents: X-ray crystal structure assisted design.

W J Thompson, P M Fitzgerald, M K Holloway, E A Emini, P L Darke, B M McKeever, W A Schleif, J C Quintero, J A Zugay, T J Tucker

Index: J. Med. Chem. 35 , 1685, (1992)

Full Text: HTML

Abstract

By tethering of a polar hydrophilic group to the P1 or P1' substituent of a Phe-based hydroxyethylene isostere, the antiviral potency of a series of HIV protease inhibitors was improved. The optimum enhancement of anti-HIV activity was observed with the 4-morpholinylethoxy substituent. The substituent effect is consistent with a model derived from inhibitor docked in the crystal structure of the native enzyme. An X-ray crystal structure of the inhibited enzyme determined to 2.25 A verifies the modeling predictions.