RESUMO
A series of IDO1 inhibitors containing a decahydroquinoline, decahydro-1,6-naphthyridine, or octahydro-1H-pyrrolo[3,2-c]pyridine scaffold were identified with good cellular and human whole blood activity against IDO1. These inhibitors contain multiple chiral centers and all diastereomers were separated. The absolute stereochemistry of each isomers were not determined. Compounds 15 and 27 stood out as leads due to their good cellular as well as human whole blood IDO1 inhibition activity, low unbound clearance, and reasonable mean residence time in rat cassette PK studies.
Assuntos
Inibidores Enzimáticos/farmacologia , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Naftiridinas/farmacologia , Pirróis/farmacologia , Quinolinas/farmacologia , Animais , Domínio Catalítico , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacocinética , Células HeLa , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/química , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Simulação de Acoplamento Molecular , Naftiridinas/síntese química , Naftiridinas/metabolismo , Naftiridinas/farmacocinética , Pirróis/síntese química , Pirróis/metabolismo , Pirróis/farmacocinética , Quinolinas/síntese química , Quinolinas/metabolismo , Quinolinas/farmacocinética , Ratos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A novel series of IDO1 inhibitors have been identified with good IDO1 Hela cell and human whole blood activity. These inhibitors contain an indoline or a 3-azaindoline scaffold. Their structure-activity-relationship studies have been explored. Compounds 37 and 41 stood out as leads due to their good potency in IDO1 Hela assay, good IDO1 unbound hWB IC50s, reasonable unbound clearance, and good MRT in rat and dog PK studies.