(Hydroxyethyl) sulfonamide HIV-1 Protease inhibitors: Identification of the 2-methylbenzoyl moiety at P-2

✍ Scribed by John N. Freskos; Deborah E. Bertenshaw; Daniel P. Getman; Robert M. Heintz; Brent V. Mischke; Lisa W. Blystone; Martin L. Bryant; Christine Funckes-Shippy; Kathyrn A. Houseman; Nandini N. Kishore; Geralyn P. Kocan; Pramod P. Mehta

• Book ID: 103983305
• Publisher: Elsevier Science
• Year: 1996
• Tongue: English
• Weight: 260 KB
• Volume: 6
• Category: Article
• ISSN: 0960-894X
• DOI: 10.1016/0960-894x(96)00035-2

✦ Synopsis

Abstrf, et : We have discovered a potent low molecular weight series of HIV-1 Protease inhibitors incorporating the (R)-(hydroxyethyl) sulfonamide isostere.

The human immunodeficiency virus type-1 (HIV-1), the causative agent of AIDS, encodes for a unique aspartyl protease, which has been shown to play a critical role in the life cycle of the virus.1 Recently, clinical trials with two different inhibitors of this protease have demonstrated a dramatic, albeit temporary, reduction in viral load and an increase in CD4 cell counts in AIDS patients. 2,3 Numerous examples of potent inhibitors of this protease have been reported and reviewed.4-6 Previously the development of potent inhibitors of this enzyme incorporating the (R)-(hydroxyethyl)urea isostere,7 and more recently, the (R)-(hydroxyethyl)sulfonamide isostere8 were reported. Due to the high potency of the sulfonamide isostere, we have been able to develop inhibitors containing relatively simple P-2 groups. Our recent disclosure of the (R)-(hydroxyethyl)sulfonamide isostere identified 2a as a potent inhibitor lead.Sa A systematic SAR study demonstrated a clear preference for the R-stereochemistry at the key hydroxyl and identified the isobutyl group as optimum for potency. Addition of a pmethoxy group, 2b, led to a furthur increase in potency. With the right side of these inhibitors optimized we then sought replacements for the Cbz group of 2b. Described herein is a series of simple benzoyl containing compounds that maintain high enzyme potency and, in certain cases, exhibt potent antiviral activity coupled with good oral bioavallability.