RESUMO
PDE8B is a cAMP-specific isoform of the broader class of phosphodiesterases (PDEs). As no selective PDE8B inhibitors had been reported, a high throughput screen was run with the goal of identifying selective tools for exploring the potential therapeutic utility of PDE8B inhibition. Of the numerous hits, one was particularly attractive since it was amenable to rapid deconstruction leading to inhibitors with very high ligand efficiency (LE) and lipophilic ligand efficiency (LLE). These triazolopyrimidines were optimized for potency, selectivity and ADME properties ultimately leading to compound 42. This compound was highly potent and selective with good bioavailability and advanced into pre-clinical development.
Assuntos
3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Diabetes Mellitus/enzimologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , 3',5'-AMP Cíclico Fosfodiesterases/metabolismo , Animais , Células Cultivadas , Diabetes Mellitus/tratamento farmacológico , Descoberta de Drogas , Inibidores Enzimáticos/metabolismo , Ensaios de Triagem em Larga Escala , Humanos , Insulina/metabolismo , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/metabolismo , Ligantes , Microssomos Hepáticos/metabolismo , Ligação Proteica , Pirimidinas/metabolismo , Ratos , Relação Estrutura-Atividade , Triazóis/química , Triazóis/metabolismo , Triazóis/farmacologiaRESUMO
A 3-amino-4-substituted pyrrolidine series of dipeptidyl peptidase IV (DPP-4) inhibitors was rapidly developed into a candidate series by identification of a polar valerolactam replacement for the lipophilic 2,4,5-trifluorophenyl pharmacophore. The addition of a gem-difluoro substituent to the lactam improved overall DPP-4 inhibition and an efficient asymmetric route to 3,4-diaminopyrrolidines was developed. Advanced profiling of a subset of analogs identified 5o with an acceptable human DPP-4 inhibition profile based on a rat PK/PD model and a projected human dose that was suitable for clinical development.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Piperidinas/uso terapêutico , Humanos , Modelos Moleculares , Piperidinas/químicaRESUMO
A series of 4-substituted proline amides was synthesized and evaluated as inhibitors of dipeptidyl pepdidase IV for the treatment of type 2 diabetes. (3,3-Difluoro-pyrrolidin-1-yl)-[(2S,4S)-(4-(4-pyrimidin-2-yl-piperazin-1-yl)-pyrrolidin-2-yl]-methanone (5) emerged as a potent (IC(50) = 13 nM) and selective compound, with high oral bioavailability in preclinical species and low plasma protein binding. Compound 5, PF-00734200, was selected for development as a potential new treatment for type 2 diabetes.
Assuntos
Inibidores da Dipeptidil Peptidase IV/farmacologia , Hipoglicemiantes/farmacologia , Pirimidinas/farmacologia , Pirrolidinas/farmacologia , Administração Oral , Animais , Cristalografia por Raios X , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/síntese química , Inibidores da Dipeptidil Peptidase IV/farmacocinética , Cães , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/farmacocinética , Pirimidinas/síntese química , Pirimidinas/farmacocinética , Pirrolidinas/síntese química , Pirrolidinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
Inhibitors of the glucagon-like peptide-1 (GLP-1) degrading enzyme dipeptidyl peptidase IV (DPP-IV) have been shown to be effective treatments for type 2 diabetes in animal models and in human subjects. A novel series of cis-2,5-dicyanopyrrolidine alpha-amino amides were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-IV) for the treatment of type 2 diabetes. 1-({[1-(Hydroxymethyl)cyclopentyl]amino}acetyl)pyrrolidine-2,5-cis-dicarbonitrile (1c) is an achiral, slow-binding (time-dependent) inhibitor of DPP-IV that is selective for DPP-IV over other DPP isozymes and proline specific serine proteases, and which has oral bioavailability in preclinical species and in vivo efficacy in animal models. The mode of binding of the cis-2,5-dicyanopyrrolidine moiety was determined by X-ray crystallography. The hydrochloride salt of 1c was further profiled for development as a potential new treatment for type 2 diabetes.
Assuntos
Inibidores de Adenosina Desaminase , Adenosina Desaminase/química , Dipeptidil Peptidase 4/química , Glicoproteínas/antagonistas & inibidores , Glicoproteínas/química , Hipoglicemiantes/síntese química , Nitrilas/síntese química , Pirrolidinas/síntese química , Administração Oral , Animais , Disponibilidade Biológica , Cristalografia por Raios X , Diabetes Mellitus Tipo 2/tratamento farmacológico , Cães , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Injeções Intravenosas , Masculino , Camundongos , Modelos Moleculares , Nitrilas/química , Nitrilas/farmacologia , Pirrolidinas/química , Pirrolidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
A series of pyrrolidine based inhibitors of dipeptidyl peptidase IV were developed from a high throughput screening hit for the treatment of type 2 diabetes. Potency, selectivity, and pharmacokinetic properties were optimized resulting in the identification of a pre-clinical candidate for further profiling.
Assuntos
Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV , Flúor/química , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Pirrolidinas/química , Pirrolidinas/farmacologia , Animais , Cristalografia por Raios X , Dipeptidil Peptidase 4/química , Cães , Humanos , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacocinética , Pirrolidinas/síntese química , Pirrolidinas/farmacocinética , Ratos , EstereoisomerismoRESUMO
Cyclohexylglycine amides of various fluorinated pyrrolidines and azetidines were prepared and tested for activity against dipeptidyl peptidase IV and in vivo in the KK mouse model of type 2 diabetes. The tetrafluoropyrrolidide, cis-3,4-difluoropyrrolidide and the fluorinated azetidides displayed unexpectedly strong activity.
Assuntos
Inibidores de Adenosina Desaminase , Amidas/síntese química , Glicoproteínas/antagonistas & inibidores , Pirrolidinas/síntese química , Inibidores de Serina Proteinase/síntese química , Amidas/farmacologia , Animais , Azetidinas , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dipeptidil Peptidase 4 , Modelos Animais de Doenças , Flúor , Teste de Tolerância a Glucose , Concentração Inibidora 50 , Camundongos , Pirrolidinas/farmacologia , Inibidores de Serina Proteinase/farmacologia , Relação Estrutura-AtividadeRESUMO
The action of glucagon in the liver is mediated by G-coupled receptors. To examine the role of glucagon in glucose homeostasis, we have generated mice in which the glucagon receptor was inactivated (GR(-/-) mice). Blood glucose levels were somewhat reduced in GR(-/-) mice relative to wild type, in both the fed and fasted state. Plasma insulin levels were not significantly affected. There was no significant effect on fasting plasma cholesterol or triglyceride levels associated with deletion of the glucagon receptor. Glucose tolerance, as assessed by an oral glucose tolerance test, improved. Plasma glucagon levels were strikingly elevated in both fed and fasted animals. Despite a total absence of glucagon receptors, these animals maintained near-normal glycemia and normal lipidemia, in the presence of circulating glucagon concentrations that were elevated by two orders of magnitude.