RESUMO
Guided by co-crystal structural information obtained from a different series we were exploring, a scaffold morphing and SBDD approach led to the discovery of the 1,4-disubstituted indazole series as a novel class of GKAs that potently activate GK in enzyme and cell assays. anti-diabetic OGTT efficacy was demonstrated with 29 in a rodent models of type 2 diabetes.
Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Descoberta de Drogas , Ativadores de Enzimas/farmacologia , Glucoquinase/metabolismo , Indazóis/farmacologia , Administração Oral , Regulação Alostérica/efeitos dos fármacos , Animais , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Relação Dose-Resposta a Droga , Ativadores de Enzimas/administração & dosagem , Ativadores de Enzimas/química , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Canais de Potássio Éter-A-Go-Go/metabolismo , Teste de Tolerância a Glucose , Humanos , Indazóis/administração & dosagem , Indazóis/química , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Modelos Moleculares , Estrutura Molecular , Bloqueadores dos Canais de Potássio/farmacologia , Relação Estrutura-AtividadeRESUMO
Methionine aminopeptidase-2 (MetAP2) is an enzyme that cleaves an N-terminal methionine residue from a number of newly synthesized proteins. This step is required before they will fold or function correctly. Pre-clinical and clinical studies with a MetAP2 inhibitor suggest that they could be used as a novel treatment for obesity. Herein we describe the discovery of a series of pyrazolo[4,3-b]indoles as reversible MetAP2 inhibitors. A fragment-based drug discovery (FBDD) approach was used, beginning with the screening of fragment libraries to generate hits with high ligand-efficiency (LE). An indazole core was selected for further elaboration, guided by structural information. SAR from the indazole series led to the design of a pyrazolo[4,3-b]indole core and accelerated knowledge-based fragment growth resulted in potent and efficient MetAP2 inhibitors, which have shown robust and sustainable body weight loss in DIO mice when dosed orally.
Assuntos
Aminopeptidases/antagonistas & inibidores , Peso Corporal/efeitos dos fármacos , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Glicoproteínas/antagonistas & inibidores , Indóis/farmacologia , Obesidade/tratamento farmacológico , Pirazóis/farmacologia , Administração Oral , Aminopeptidases/metabolismo , Animais , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Glicoproteínas/metabolismo , Humanos , Indóis/administração & dosagem , Indóis/química , Metionil Aminopeptidases , Camundongos , Camundongos Obesos , Modelos Moleculares , Estrutura Molecular , Pirazóis/administração & dosagem , Pirazóis/química , Relação Estrutura-AtividadeRESUMO
Methionine aminopeptidase 2 (MetAP2) is an enzyme that cleaves an N-terminal methionine residue from a number of newly synthesized proteins. Pre-clinical and clinical studies suggest that MetAP2 inhibitors could be used as a novel treatment for obesity. Herein we describe our use of fragment screening methods and structural biology to quickly identify and elaborate an indazole fragment into a series of reversible MetAP2 inhibitors with <10nM potency, excellent selectivity, and favorable in vitro safety profiles.
Assuntos
Aminopeptidases/antagonistas & inibidores , Peso Corporal/efeitos dos fármacos , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Glicoproteínas/antagonistas & inibidores , Indazóis/farmacologia , Obesidade/tratamento farmacológico , Administração Oral , Aminopeptidases/metabolismo , Animais , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Glicoproteínas/metabolismo , Humanos , Indazóis/síntese química , Indazóis/química , Metionil Aminopeptidases , Camundongos , Camundongos Obesos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Guided by co-crystal structures of compounds 15, 22 and 30, an SBDD approach led to the discovery of the 6-methyl pyridone series as a novel class of GKAs that potently activate GK in enzyme and cell assays. Anti-diabetic OGTT efficacy was demonstrated with 54 in a mouse model of type 2 diabetes.
Assuntos
Diabetes Mellitus Experimental/enzimologia , Desenho de Fármacos , Ativadores de Enzimas/farmacologia , Glucoquinase/metabolismo , Hipoglicemiantes/farmacologia , Piridonas/farmacologia , Animais , Cristalografia por Raios X , Diabetes Mellitus Experimental/tratamento farmacológico , Modelos Animais de Doenças , Ativação Enzimática/efeitos dos fármacos , Ativadores de Enzimas/administração & dosagem , Ativadores de Enzimas/química , Teste de Tolerância a Glucose , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/química , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Modelos Moleculares , Estrutura Molecular , Piridonas/administração & dosagem , Piridonas/química , Relação Estrutura-AtividadeRESUMO
The mTOR kinase regulates a variety of critical cellular processes and has become a target for the treatment of various cancers. Using a combination of property-based drug design and Free-Wilson analysis, we further optimized a series of selective mTOR inhibitors based on the (S)-6a-methyl-6a,7,9,10-tetrahydro[1,4]oxazino[3,4-h]pteridin-6(5H)-one scaffold. Our efforts resulted in 14c, which showed similar in vivo efficacy compared to previous lead 1 at 1/15 the dose, a result of its improved drug-like properties.