RESUMO
We discovered novel pyrrolidine MCHR1 antagonist 1 possessing moderate potency. Profiling of pyrrolidine 1 demonstrated that it was an inhibitor of the hERG channel. Investigation of the structure-activity relationship of this class of pyrrolidines allowed us to optimize the MCHR1 potency and decrease the hERG inhibition. Increasing the acidity of the amide proton by converting the benzamide in lead 1 to an anilide provided single digit nanomolar MCHR1 antagonists while replacing the dimethoxyphenyl ring of 1 with alkyl groups possessing increased polarity dramatically reduced the hERG inhibition.
Assuntos
Canais de Potássio Éter-A-Go-Go/metabolismo , Pirrolidinas/química , Receptores de Somatostatina/antagonistas & inibidores , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Humanos , Pirrolidinas/síntese química , Pirrolidinas/farmacologia , Receptores de Somatostatina/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A series of 4,5-disubstituted cis-pyrrolidinones was investigated as inhibitors of 17beta-HSD II for the treatment of osteoporosis. Biochemical data for several compounds are given. Compound 42 was selected as the lead candidate.
Assuntos
17-Hidroxiesteroide Desidrogenases/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Pirrolidinonas/química , Pirrolidinonas/farmacologia , Tiofenos/química , Tiofenos/farmacologia , 17-Hidroxiesteroide Desidrogenases/metabolismo , Animais , Linhagem Celular , Inibidores Enzimáticos/química , Humanos , Concentração Inibidora 50 , Macaca fascicularis , Pirrolidinonas/síntese química , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Tiofenos/síntese químicaRESUMO
4,5-Disubstituted cis-pyrrolidinones were investigated as inhibitors of type II 17beta-hydroxysteroid dehydrogenase (17beta-HSD). Early structure-activity relationship patterns for this class of compounds are discussed.
Assuntos
17-Hidroxiesteroide Desidrogenases/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Pirrolidinonas/farmacologia , 17-Hidroxiesteroide Desidrogenases/metabolismo , Inibidores Enzimáticos/química , Humanos , Pirrolidinonas/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
New inhibitors of palmitoyl-CoA oxidation are based on the introduction of nitrogen heterocycles in the 'Western Portion' of the molecule. SAR studies led to the discovery of CVT-4325 (shown), a potent FOXi (IC50=380 nM rat mitochondria) with favorable PK properties (F=93%, t(1/2)=13.6h, dog).
Assuntos
Antioxidantes/farmacologia , Antioxidantes/farmacocinética , Ácidos Graxos/metabolismo , Oxidiazóis/farmacologia , Oxidiazóis/farmacocinética , Palmitoil Coenzima A/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Cães , Ácidos Graxos/química , Humanos , Conformação Molecular , Oxirredução/efeitos dos fármacos , Palmitoil Coenzima A/metabolismo , Ratos , Relação Estrutura-AtividadeRESUMO
Bis-aryl ureas have been disclosed previously as a potent class of Raf kinase inhibitors. Modifications in the amide portion led to an improvement in aqueous solubility, an important characteristic for an oral drug. Based on this finding, we hypothesize that this portion of the molecule is directed towards the solvent in Raf-1.
