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.
Assuntos
Lactamas/química , Pirrolidinonas/química , Receptores de Prostaglandina E/agonistas , Lactamas/metabolismo , Ligação Proteica , Pirrolidinonas/metabolismo , Receptores de Prostaglandina E/metabolismo , Receptores de Prostaglandina E Subtipo EP4 , EstereoisomerismoRESUMO
CC-chemokine receptor 3 (CCR3)-stimulating chemokines are likely to have important in vivo roles in the regulation of eosinophil, basophil, and potentially helper T cell type 2 and mast cell recruitment. We have developed techniques to investigate the actions of eotaxin and other chemokines on multiple leukocyte populations in whole blood, without cell purification steps that might alter leukocyte responsiveness. We have shown that the potency of eotaxin in whole blood is limited by Duffy antigen binding, which may modulate the actions of this chemokine in vivo. We have also investigated the efficacy and potency of a new panel of small molecule antagonists of CCR3 on responses of eosinophils, neutrophils, basophils, and monocytes to chemokines, using whole blood assays of shape change, chemokine receptor internalization, and CD11b upregulation. These small molecule antagonists cause selective and potent inhibition of CCR3 on eosinophils and basophils, are bioavailable in blood, and are prototypic antagonists potentially of benefit in the treatment of human allergic disease. Such whole blood methods may also be employed in the investigation of other small molecule chemokine receptor antagonists.