RESUMO
The syntheses and SAR investigations of novel CB(1) receptor antagonists based on a 1,2-diaryl piperidine core have been described. Optimization of this core afforded a compound with robust in vivo potency by reducing food intake in a mouse DIO model.
Assuntos
Piperidinas/química , Piperidinas/farmacologia , Receptor CB1 de Canabinoide/antagonistas & inibidores , Animais , Dieta/efeitos adversos , Ingestão de Alimentos/efeitos dos fármacos , Ingestão de Alimentos/fisiologia , Camundongos , Camundongos Obesos , Obesidade/etiologia , Obesidade/metabolismo , Piperidinas/administração & dosagem , Ligação Proteica/fisiologia , Receptor CB1 de Canabinoide/metabolismo , Relação Estrutura-AtividadeRESUMO
CB1 receptor antagonists have proven to be clinically effective in treating obesity and related disorders. We report here the identification of a novel class of azetidinone CB1 antagonists by using virtual screening methods. For this purpose, we developed a pharmacophore model based on known representative CB1 antagonists and employed it to screen a database of about a half million Schering-Plough compounds. We applied a stepwise filtering protocol based on molecular weight, compound availability, and a modified rule-of-five to reduce the number of hits. We then combined Bayesian modeling and clustering techniques to select a final set of 420 compounds for in vitro testing. Five compounds were found to have >50% inhibition at 100 nM in a CB1 competitive binding assay and were further characterized by using both CB1 and CB2 assays. The most potent compound has a CB1 K i of 53 nM and >5-fold selectivity against the CB2 receptor.
Assuntos
Avaliação Pré-Clínica de Medicamentos , Receptor CB1 de Canabinoide/antagonistas & inibidores , Teorema de Bayes , Modelos Moleculares , Ligação Proteica , Receptor CB1 de Canabinoide/metabolismoRESUMO
The structure-activity relationship (SAR) of the vinyl pyridine region of himbacine derived thrombin receptor (PAR-1) antagonists is described. A 2-vinylpyridyl ring substituted with an aryl or a heteroaryl group at the 5-position showed the best overall PAR-1 affinity and pharmacokinetic properties. One of the newly discovered analogs bearing a 5-(3-pyridyl) substituent showed excellent PAR-1 affinity (Ki = 22 nM) and oral activity with reduced ClogP and improved off-target selectivity compared to an earlier development candidate.
Assuntos
Alcaloides/química , Alcaloides/farmacologia , Furanos/química , Furanos/farmacologia , Naftalenos/química , Naftalenos/farmacologia , Piperidinas/química , Piperidinas/farmacologia , Receptor PAR-1/antagonistas & inibidores , Animais , Anticoagulantes/química , Anticoagulantes/farmacologia , Estrutura Molecular , Inibidores da Agregação Plaquetária/química , Inibidores da Agregação Plaquetária/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
The structure-activity relationship (SAR) of the lactone ring of himbacine derived thrombin receptor (PAR-1) antagonists (e.g., 2-5) is described. The effect of the lactone carbonyl group on binding to PAR-1 is dependent on the substitution pattern of the pyridine ring. A stereoselective intramolecular Michael addition reaction to the vinyl pyridine group was observed for these pyridine analogs of himbacine in basic conditions at elevated temperature.