AIDSWEEKLY Plus, Monday, December 15, 1997.
Daniel J. DeNoon, Senior Editor
A new protease inhibitor, currently in early clinical studies, is effective against HIV strains resistant to ritonavir (Norvir, Abbott).
The drug, code named PNU-140690, is a third-generation non-peptidic derivative of coumarin. It is a sulfonamide- containing 5,6-dihydro-4-hydroxy-2-pyrone.
In vitro studies show that PNU-140690 is equally effective against ritonavir-sensitive and ritonavir-resistant strains of HIV-1. Moreover, the new drug has additive-to-moderately- synergistic effects in combination with ritonavir - even against ritonavir-resistant virus.
"These data suggest that PNU-140690 may be useful in combination regimens with a structurally unrelated protease inhibitor such as ritonavir," wrote Upjohn researchers K.-T. Chong and P.J. Pagano in the journal Antimicrobial Agents and Chemotherapy ("In Vitro Combination of PNU-140690, a Human Immunodeficiency Virus Type 1 Protease Inhibitor, with Ritonavir against Ritonavir-Sensitive and -Resistant Clinical Isolates," Antimic Ag Chem, 1997;41(11):2367-73).
Development of PNU-140690 was announced at the 1996 International Conference on AIDS by Upjohn researcher S. Thaisrivongs.
"The third-generation non-peptidic compounds were identified in the dihydropyrone class, [with] potent inhibition of HIV protease (K[i]; 0.05 nM), high antiviral activity (IC[50]= 50 nM in HIV-1[IIIB] infected H9 or MT4 cells; IC[50]= 30 nM in HIV-1[JRCSF] infected PBMC; and IC[90] (median)= 0.3 (micro)M against a panel of 10 AZT-resistant clinical HIV isolates in PBMC)," Thaisrivongs and colleagues wrote in their presentation abstract. "In an assay medium with added 75 percent human plasma, there was an approximately half-a-log-unit increase in the IC[50] value. After oral administration to dogs (C[max]= 26 (micro)M at 10 mg/kg), the bioavailability was 40 percent."
The corresponding authors for this study are K.-T. Chong and P.J. Pagano, Infectious Diseases Research, Pharmacia & Upjohn Inc., Kalamazoo, Michigan 49001.
Published by Charles Henderson, Publisher. Editorial & Publishing Office: P.O. Box 5528, Atlanta, GA 30307-0528 / Telephone: (800) 633-4931; Subscription Office: P.O. Box 830409, Birmingham, AL 35283-0409 / FAX: (205) 995-1588 - by Daniel J. DeNoon, Senior Editor
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Published by Charles Henderson, Publisher. Editorial & Publishing Office: P.O. Box 5528, Atlanta, GA 30307-0528 / Telephone: (800) 633-4931; Subscription Office: P.O. Box 830409, Birmingham, AL 35283-0409 / FAX: (205) 995-1588 http://www.newsfile.com
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