(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-1(IIIB) WITH REDUCED REPLICATION PHENOTYPES

The (alkylamino) piperidine bis(heteroaryl)piperizines (AAP-BHAPs) are a new class of human immunodeficiency virus type 1 (HIV-1)-specific i nhibitors which were identified by targeted screening of recombinant r everse transcriptase (RT) enzymes carrying key nonnucleoside reverse t ranscriptase inhibitor (NNRTI) resistance-conferring mutations and NNR TI-resistant variants of HIV-l. Phenotypic profiling of the two most p otent AAP-BHAPs, U-95133 and U-104489, against in vitro-selected drug- resistant HIV-1 variants carrying the NNRTI resistance-conferring muta tion (Tyr-->Cys) at position 181 of the HIV-1 RT revealed submicromola r 90% inhibitory concentration estimates for these compounds, Moreover , U-104489 demonstrated potent activity against BHAP-resistant HIV-1(M F) harboring the Pro-236-->Leu RT substitution and significantly suppr essed the replication of clinical isolates of HIV-1 resistant to both delavirdine (BHAP U-90152T) and zidovudine, Biochemical and phenotypic characterization of AAP-BHAP-resistant HIV-1(IIIB) 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 integr ity and enzymatic activity of virion-associated RT heterodimers, as we ll as the replication capacity of these resistant viruses.