RESUMO
Glucokinase (GK) is a key regulator of glucose homeostasis, and its small-molecule activators represent a promising opportunity for the treatment of type 2 diabetes. Several GK activators have been advanced into clinical trials and have demonstrated promising efficacy; however, hypoglycemia represents a key risk for this mechanism. In an effort to mitigate this hypoglycemia risk while maintaining the efficacy of the GK mechanism, we have investigated a series of amino heteroaryl phosphonate benzamides as ''partial" GK activators. The structure-activity relationship studies starting from a "full GK activator" 11, which culminated in the discovery of the "partial GK activator" 31 (BMS-820132), are discussed. The synthesis and in vitro and in vivo preclinical pharmacology profiles of 31 and its pharmacokinetics (PK) are described. Based on its promising in vivo efficacy and preclinical ADME and safety profiles, 31 was advanced into human clinical trials.
Assuntos
Azetidinas , Diabetes Mellitus Tipo 2 , Hipoglicemia , Organofosfonatos , Azetidinas/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucoquinase , Humanos , Hipoglicemia/tratamento farmacológico , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Organofosfonatos/farmacologia , Organofosfonatos/uso terapêuticoRESUMO
Several pyrazolo-, triazolo-, and imidazolopyrimidines were synthesized and evaluated as inhibitors of DPP4. Of these three classes of compounds, the imidazolopyrimidines displayed the greatest potency and demonstrated excellent selectivity over the other dipeptidyl peptidases. SAR evaluation for these scaffolds was described as they may represent potential treatments for type 2 diabetes.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/síntese química , Inibidores de Proteases/síntese química , Pirimidinas/química , Dipeptidil Peptidase 4/metabolismo , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/uso terapêutico , Inibidores de Proteases/química , Inibidores de Proteases/uso terapêutico , Pirimidinas/síntese química , Pirimidinas/uso terapêutico , Relação Estrutura-AtividadeRESUMO
The synthesis and SAR of aminomethyl-substituted imidazolopyrimidine DPP4 inhibitors bearing varied pendant aryl groups is described. Compound 1, which exists as a separable mixture of non-interconvertible atropisomers was used as the starting point for investigation. The effects of substituent pattern and type as well as stereochemical effects on inhibitor potency are discussed.
Assuntos
Inibidores da Dipeptidil Peptidase IV/síntese química , Inibidores da Dipeptidil Peptidase IV/farmacologia , Imidazóis/síntese química , Imidazóis/farmacologia , Pirimidinas/síntese química , Pirimidinas/farmacologia , Domínio Catalítico , Dipeptidases/antagonistas & inibidores , Inibidores da Dipeptidil Peptidase IV/química , Dipeptidil Peptidases e Tripeptidil Peptidases/antagonistas & inibidores , Indicadores e Reagentes , Isomerismo , Cinética , Modelos Moleculares , Solventes , Relação Estrutura-AtividadeRESUMO
Continued structure-activity relationship (SAR) exploration within our previously disclosed azolopyrimidine containing dipeptidyl peptidase-4 (DPP4) inhibitors led us to focus on an imidazolopyrimidine series in particular. Further study revealed that by replacing the aryl substitution on the imidazole ring with a more polar carboxylic ester or amide, these compounds displayed not only increased DPP4 binding activity but also significantly reduced human ether-a-go-go related gene (hERG) and sodium channel inhibitory activities. Additional incremental adjustment of polarity led to permeable molecules which exhibited favorable pharmacokinetic (PK) profiles in preclinical animal species. The active site binding mode of these compounds was determined by X-ray crystallography as exemplified by amide 24c. A subsequent lead molecule from this series, (+)-6-(aminomethyl)-5-(2,4-dichlorophenyl)-N-(1-ethyl-1H-pyrazol-5-yl)-7-methylimidazo[1,2-a]pyrimidine-2-carboxamide (24s), emerged as a potent, selective DPP4 inhibitor that displayed excellent PK profiles and in vivo efficacy in ob/ob mice.
Assuntos
Inibidores da Dipeptidil Peptidase IV , Hipoglicemiantes/síntese química , Imidazóis/síntese química , Pirimidinas/síntese química , Animais , Domínio Catalítico , Cristalografia por Raios X , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dipeptidil Peptidase 4/química , Cães , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Humanos , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Imidazóis/farmacocinética , Imidazóis/farmacologia , Masculino , Camundongos , Camundongos Obesos , Modelos Moleculares , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Ratos , Bloqueadores dos Canais de Sódio/farmacologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Based on the scaffold of the pharmacologically selective thyromimetic 2b, structurally a close analog to KB-141 (2a), a number of novel N-acylated-alpha-amino acid derivatives were synthesized and tested in a TR radioligand binding assay as well as in a reporter cell assay. On the basis of TRbeta(1)-isoform selectivity and affinity, as well as affinity to the reporter cell assay, 3d was selected for further studies in the cholesterol-fed rat model. In this model 3d revealed an improved therapeutic window between cholesterol and TSH lowering but decreased margins versus tachycardia compared with 2a.