ABSTRACT
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.
Subject(s)
Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacology , HIV Reverse Transcriptase/antagonists & inhibitors , HIV-1/drug effects , HIV-1/enzymology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Anti-HIV Agents/chemical synthesis , Drug Resistance, Viral , HIV Infections/drug therapy , HIV Reverse Transcriptase/metabolism , HIV-1/genetics , Humans , Models, Molecular , Mutation , Piperidines/chemical synthesis , Piperidines/chemistry , Piperidines/pharmacology , Pyrimidines/chemical synthesis , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
HIV Reverse Transcriptase/antagonists & inhibitors , HIV-1/drug effects , Mutation , Pyrimidines/pharmacology , Reverse Transcriptase Inhibitors/pharmacology , Drug Discovery , Drug Resistance, Viral/genetics , HIV-1/genetics , Models, Molecular , Pyrimidines/chemistry , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
HIV Reverse Transcriptase/antagonists & inhibitors , Pyridazines , Reverse Transcriptase Inhibitors , Animals , Dogs , Drug Resistance, Viral/drug effects , Inhibitory Concentration 50 , Molecular Structure , Pyridazines/chemical synthesis , Pyridazines/chemistry , Pyridazines/pharmacology , Rats , Reverse Transcriptase Inhibitors/chemical synthesis , Reverse Transcriptase Inhibitors/chemistry , Reverse Transcriptase Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
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.
