RESUMO
Structure-guided lead optimization of recently described benzimidazolyl acetamides addressed the key liabilities of the previous lead compound 1. These efforts culminated in the discovery of 4-{(S)-2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-acetylamino}-3-fluoro-benzoic acid 7g, a highly potent and selective FXR agonist with excellent physicochemical and ADME properties and potent lipid lowering activity after oral administration to LDL receptor deficient mice.
Assuntos
Benzimidazóis/química , Receptores Citoplasmáticos e Nucleares/agonistas , para-Aminobenzoatos , Ácido 4-Aminobenzoico/síntese química , Ácido 4-Aminobenzoico/química , Ácido 4-Aminobenzoico/farmacocinética , Administração Oral , Animais , Benzimidazóis/síntese química , Benzimidazóis/farmacocinética , Sítios de Ligação , Simulação por Computador , Cristalografia por Raios X , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microssomos Hepáticos/metabolismo , Conformação Molecular , Ratos , Ratos Wistar , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores de LDL/deficiência , Receptores de LDL/genética , Receptores de LDL/metabolismo , Relação Estrutura-AtividadeRESUMO
A novel series of potent histamine H(3) receptor inverse agonists based on the 3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one scaffold has been discovered. Several compounds display high selectivity over other histamine receptor subtypes and have favorable physicochemical properties, low potential for CYP450 enzyme inhibition and high metabolic stability in microsomal preparations. (R)-2-Cyclopropylmethyl-8-(1-isopropyl-piperidin-4-yloxy)-3-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (8t) showed good in vivo efficacy after per os application in an acute rat dipsogenia model of water intake.
Assuntos
Indóis/química , Receptores Histamínicos H3/química , Animais , Diabetes Insípido/tratamento farmacológico , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Agonismo Inverso de Drogas , Humanos , Indóis/síntese química , Indóis/uso terapêutico , Microssomos Hepáticos/metabolismo , Modelos Químicos , Ratos , Receptores Histamínicos H3/genética , Receptores Histamínicos H3/metabolismo , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/metabolismoRESUMO
Further lead optimization efforts on previously described 1,2,3,4,10,10a-hexahydro-1H-pyrazino[1,2-a]indoles led to the new class of 5,5a,6,7,8,9-hexahydro-pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazines culminating in the discovery of (5aR,9R)-2-[(cyclopropylmethoxy)methyl]-5,5a,6,7,8,9-hexahydro-9-methyl-pyrido[3', 2':4,5]pyrrolo[1,2-a]pyrazine 18 as a potent, full 5-HT(2C) receptor agonist with an outstanding selectivity profile and excellent hERG and phospholipidosis properties.