RESUMO
Recently, a new class of HIV reverse transcriptase (HIV-RT) inhibitors has been reported. The novel mechanism of inhibition by this class involves competitive binding to the active site of the RT enzyme and has been termed Nucleotide-Competing Reverse Transcriptase Inhibitors (NcRTIs). In this publication we describe the optimization of a novel benzofurano[3,2-d]pyrimidin-2-one series of NcRTIs. The starting point for the current study was inhibitor 2, which had high biochemical and antiviral potency but only moderate permeability in a Caco-2 assay and high B-to-A efflux, resulting in moderate rat bioavailability and low Cmax. We present herein the results and strategies we employed to optimize both the potency as well as the permeability, metabolic stability and pharmacokinetic profile of this series. One of the key observations of the present study was the importance of shielding polar functionality, at least in the context of the current chemotype, to enhance permeability. These studies led to the identification of inhibitors 39 and 45, which display sub-nanomolar antiviral potency in a p24 ELISA assay with significantly reduced efflux ratios (ratios <1.5). These inhibitors also display excellent rat pharmacokinetic profiles with high bioavailabilities and low clearance.
Assuntos
Antivirais/farmacologia , Benzofuranos/farmacologia , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV/efeitos dos fármacos , Pirimidinonas/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Administração Oral , Animais , Antivirais/administração & dosagem , Antivirais/química , Benzofuranos/química , Disponibilidade Biológica , Células CACO-2 , Relação Dose-Resposta a Droga , Transcriptase Reversa do HIV/metabolismo , Humanos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Pirimidinonas/administração & dosagem , Pirimidinonas/química , Ratos , Inibidores da Transcriptase Reversa/administração & dosagem , Inibidores da Transcriptase Reversa/química , Relação Estrutura-AtividadeRESUMO
For a series of beta-homophenylalanine based inhibitors of dipeptidyl peptidase IV ADME properties were improved by the incorporation of amide replacements. These efforts led to a novel series of potent and selective inhibitors of DPP-4 that exhibit an attractive pharmacokinetic profile and show excellent efficacy in an animal model of diabetes.
Assuntos
Amidas/química , Aminobutiratos/química , Inibidores da Dipeptidil Peptidase IV , Relação Estrutura-Atividade , Amidas/antagonistas & inibidores , Células CACO-2 , Linhagem Celular Tumoral , Química Farmacêutica , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Desenho de Fármacos , Humanos , Hipoglicemiantes/antagonistas & inibidores , Hipoglicemiantes/uso terapêutico , Inibidores de Proteases/farmacocinética , Inibidores de Proteases/farmacologia , Canais de Sódio/metabolismoRESUMO
A series of highly potent and selective inhibitors of DPP-4 was optimized for ADMET properties. The effort resulted in the discovery of inhibitor 1g, that exhibits excellent efficacy in an oral glucose tolerance test and an attractive pharmacokinetic profile.
Assuntos
Aminobutiratos/química , Inibidores da Dipeptidil Peptidase IV , Hidrocarbonetos Fluorados/química , Hipoglicemiantes/química , Inibidores de Proteases/química , Pirrolidinas/química , Administração Oral , Aminobutiratos/síntese química , Aminobutiratos/farmacocinética , Animais , Células CACO-2 , Linhagem Celular Tumoral , Dipeptidil Peptidase 4/metabolismo , Cães , Humanos , Hidrocarbonetos Fluorados/síntese química , Hidrocarbonetos Fluorados/farmacologia , Hipoglicemiantes/síntese química , Hipoglicemiantes/farmacocinética , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacocinética , Pirrolidinas/síntese química , Pirrolidinas/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
The co-crystal structure of beta-phenethylamine fragment inhibitor 5 bound to DPP-IV revealed that the phenyl ring occupied the proline pocket of the enzyme. This finding provided the basis for a general hypothesis of a reverse binding mode for beta-phenethylamine-based DPP-IV inhibitors. Novel inhibitor design concepts that obviate substrate-like structure-activity relationships (SAR) were thereby enabled, and novel, potent inhibitors were discovered.