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J. Virol., Jun 1996, 3698-3705, Vol 70, No. 6
Copyright © 1996, American Society for Microbiology

(Alkylamino) piperidine bis(heteroaryl)piperizine analogs are potent, broad-spectrum nonnucleoside reverse transcriptase inhibitors of drug- resistant isolates of human immunodeficiency virus type 1 (HIV-1) and select for drug-resistant variants of HIV-1IIIB with reduced replication phenotypes

RA Olmsted, DE Slade, LA Kopta, SM Poppe, TJ Poel, SW Newport, KB Rank, C Biles, RA Morge, TJ Dueweke, Y Yagi, DL Romero, RC Thomas, SK Sharma and WG Tarpley
Cancer and Infectious Diseases Research, Pharmacia & Upjohn, Kalamazoo, Michigan 49001.

The (alkylamino)piperidine bis(heteroaryl)piperizines (AAP-BHAPs) are a new class of human immunodeficiency virus type 1 (HIV-1)-specific inhibitors which were identified by targeted screening of recombinant reverse transcriptase (RT) enzymes carrying key nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance-conferring mutations and NNRTI-resistant variants of HIV-1. Phenotypic profiling of the two most potent AAP-BHAPs, U-95133 and U-104489, against in vitro-selected drug- resistant HIV-1 variants carrying the NNRTI resistance-conferring mutation (Tyr->Cys) at position 181 of the HIV-1 RT revealed submicromolar 90% inhibitory concentration estimates for these compounds. Moreover, U-104489 demonstrated potent activity against BHA- P-resistant HIV-1MF harboring the Pro-236->Leu RT substitution and significantly suppressed the replication of clinical isolates of HIV-1 resistant to both delavirdine (BHAP U-90152T) and zidovudine. Biochemical and phenotypic characterization of AAP-BHAPresistant HIV- 1IIIB variants revealed that high-level resistance to the AAP-BHAPs was mediated by a Gly-190->Glu substitution in RT, which had a deleterious effect on the integrity and enzymatic activity of virion-associated RT heterodimers, as well as the replication capacity of these resistant viruses.

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