Tomich PK, Thaisrivongs S, Aristoff P, Romines K, Howe J, Watenpaugh K, Chong KT, Kezdy F, Tomich CS, Tomasselli A, Tarpley G; International Conference on AIDS.

Int Conf AIDS. 1996 Jul 7-12; 11: 69 (abstract no. Mo.A.1084).

Chemical & Biological Screening, Upjohn Laboratories, Pharmacia & Upjohn, Inc., Kalamazoo, MI. Fax: 616-385-5225.

Objectives: Having previously introduced two generations of orally bioavailable, nonpeptidic HIV protease inhibitors (the pyrone U-96988 and the cyclooctylpyrone U-103017) into phase I clinical trials (in 1993 and 1994, respectively), the next goal was to design and optimize orally bioavailable third-generation nonpeptidic inhibitors with good pharmacokinetic (PK) properties with significantly improved antiviral potencies. Methods: Analogs were assayed for inhibitory activity against purified HIV protease. A novel analysis for determination of Ki values from this end-point assay will be described. The dimeric, tandem and various mutant forms (V82A and V82F/I84V) of HIV-1 and the dimeric form of HIV-2 enzymes were used to assess increased affinity and utility. A series of inhibitors were simultaneously evaluated in crystal structures complexed with the HIV protease that assisted the structure-based design effort. They were also assessed in HIV-1IIIB infected H9 cells and HIV-1JRCSF infected PBMC antiviral assays. Results: Using a novel end-point kinetic analysis, Ki values were determined with a variety of HIV enzyme structures. The dihydropyrone compound class proved especially productive. Within error, those inhibitors tested had equivalent affinities with the various forms of HIV-1 protease and HIV-2 protease. A linear correlation between Ki values and calculated binding energies based upon structures was observed with the HIV-2 enzyme. Third-generation nonpeptidic dihydropyrone compounds were identified as potent inhibitors of HIV protease (Ki value less than 50 pM) and demonstrated high antiviral activity (IC50 value of 50 nM in HIV-1IIIB infected H9 cells; and IC50 value of 30 nM in HIV-1JRCSF infected PBMC). Conclusions: Orally bioavailable, third-generation, nonpeptidic HIV protease inhibitors have been optimized with in vitro antiviral potency comparable to the peptide-derived inhibitors saquinavir, indinavir, and ritonavir. In preliminary studies isolates with much reduced sensitivity to the peptide-derived inhibitors remain sensitive to this class of unique, nonpeptidic compounds. A few dihydropyrone inhibitors have been under extensive preclinical safety studies and are targeted for clinical evaluation in the second half of 1996.

Publication Types:

• Meeting Abstracts

Keywords:

• Acquired Immunodeficiency Syndrome
• Antiviral Agents
• HIV Infections
• HIV Protease
• HIV Protease Inhibitors
• HIV Seropositivity
• HIV-1
• HIV-2
• In Vitro
• Indinavir
• Pyrones
• Ritonavir
• Saquinavir
• U 103017
• U 96988

Other ID:

• 96921154

UI: 102217053

From Meeting Abstracts