RESUMO
A variety of analogues of 1-[4-methoxy-3,5-dimethylbenzyl]-4-[3-(ethylamino)-2-pyridyl]piperazine hydrochloride (U-80493E) were synthesized and evaluated for their inhibition of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT). Replacement of the substituted aryl moiety with various substituted indoles provided bis(heteroaryl)piperazines (BHAPs) that were 10-100-fold more potent than U-80493E. The pyridyl portion of the lead molecule was found to be very sensitive to modifications. Extensive preclinical evaluations of several of these compounds led to the selection of 1-[(5-methoxyindol-2-yl)carbonyl]-4-[3-(ethylamino)-2- pyridyl]piperazine methanesulfonate (U-87201E, atevirdine mesylate) for clinical evaluation.
Assuntos
Antivirais/síntese química , HIV-1/enzimologia , Piperazinas/síntese química , Inibidores da Transcriptase Reversa , Aminopiridinas/química , Aminopiridinas/farmacologia , Antivirais/farmacologia , Células Cultivadas , Transcriptase Reversa do HIV , Humanos , Estrutura Molecular , Piperazinas/química , Piperazinas/farmacologiaRESUMO
A novel class of bis(heteroaryl)piperazine (BHAP) analogs which possesses the ability to inhibit NNRTI (non-nucleoside reverse transcriptase inhibitor) resistant recombinant HIV-1 reverse transcriptase (RT) and NNRTI resistant variants of HIV-1 has been identified via targeted screening. Further investigation of the structure-activity relationships of close congeners of these novel (alkylamino)piperidine BHAPs (AAP-BHAPs) led to the synthesis of several compounds possessing the desired phenotype (e.g., activity against recombinant RTs carrying the Y181C and P236L substitutions). Further structural modifications were required to inhibit metabolism and modulate solubility in order to obtain compounds with the desired biological profile as well as appropriate pharmaceutical properties. The AAP-BHAPs with the most suitable characteristics were compounds 7, 15, and 36.
Assuntos
Fármacos Anti-HIV/síntese química , Resistência Microbiana a Medicamentos , HIV-1/efeitos dos fármacos , Indóis/farmacologia , Piperazinas/farmacologia , Inibidores da Transcriptase Reversa/síntese química , Animais , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/farmacologia , Disponibilidade Biológica , Linhagem Celular , Delavirdina , Estabilidade de Medicamentos , Transcriptase Reversa do HIV , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/farmacocinética , Piperidinas/farmacologia , Piridinas/síntese química , Piridinas/farmacocinética , Piridinas/farmacologia , Ratos , Inibidores da Transcriptase Reversa/farmacocinética , Inibidores da Transcriptase Reversa/farmacologia , Relação Estrutura-AtividadeRESUMO
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.