RESUMO
Further investigation of the recently reported piperidine-4-yl-aminopyrimidine class of non-nucleoside reverse transcriptase inhibitors (NNRTIs) has been carried out. Thus, preparation of a series of N-phenyl piperidine analogs resulted in the identification of 3-carboxamides as a particularly active series. Analogs such as 28 and 40 are very potent versus wild-type HIV-1 and a broad range of NNRTI-resistant mutant viruses. Synthesis, structure-activity relationship (SAR), clearance data, and crystallographic evidence for the binding motif are discussed.
Assuntos
Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , Pirimidinas/química , Pirimidinas/farmacologia , Fármacos Anti-HIV/síntese química , Farmacorresistência Viral , Infecções por HIV/tratamento farmacológico , Transcriptase Reversa do HIV/metabolismo , HIV-1/genética , Humanos , Modelos Moleculares , Mutação , Piperidinas/síntese química , Piperidinas/química , Piperidinas/farmacologia , Pirimidinas/síntese química , Relação Estrutura-AtividadeRESUMO
An analysis of the binding motifs of known HIV-1 non-nucleoside reverse transcriptase inhibitors has led to discovery of novel piperidine-linked aminopyrimidine derivatives with broad activity against wild-type as well as drug-resistant mutant viruses. Notably, the series retains potency against the K103N/Y181C and Y188L mutants, among others. Thus, the N-benzyl compound 5k has a particularly attractive profile. Synthesis and SAR are presented and discussed, as well as crystal structures relating to the binding motifs.
Assuntos
Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Mutação , Pirimidinas/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Descoberta de Drogas , Farmacorresistência Viral/genética , HIV-1/genética , Modelos Moleculares , Pirimidinas/química , Relação Estrutura-AtividadeRESUMO
A series of benzyl pyridazinones were evaluated as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Several members of this series showed good activity against the wild-type virus and NNRTI-resistant viruses. The binding of inhibitor 5a to HIV-RT was analyzed by surface plasmon resonance spectroscopy. Pharmacokinetic studies of 5a in rat and dog demonstrated that this compound has good oral bioavailability in animal species. The crystal structure of a complex between HIV-RT and inhibitor 4c is also described.
Assuntos
Transcriptase Reversa do HIV/antagonistas & inibidores , Piridazinas , Inibidores da Transcriptase Reversa , Animais , Cães , Farmacorresistência Viral/efeitos dos fármacos , Concentração Inibidora 50 , Estrutura Molecular , Piridazinas/síntese química , Piridazinas/química , Piridazinas/farmacologia , Ratos , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/farmacologia , Relação Estrutura-AtividadeRESUMO
A series of 7-[(5R)-substituted 2-oxo-1-pyrrolidinyl]-heptanoic acids were prepared, their isomeric purity determined, and pharmacologically evaluated. Lactams with affinity for the EP(4) receptor displayed agonist behavior. The lower side-chain of the lactam template could be substituted to afford ligands (e.g., 17, 24, 30, 31, and 33) of high potency and greater than 1000-fold affinity for EP(4) versus the other EP prostanoid receptors.