RESUMO
Modulation of gastrointestinal nutrient sensing pathways provides a promising a new approach for the treatment of metabolic diseases including diabetes and obesity. The calcium-sensing receptor has been identified as a key receptor involved in mineral and amino acid nutrient sensing and thus is an attractive target for modulation in the intestine. Herein we describe the optimization of gastrointestinally restricted calcium-sensing receptor agonists starting from a 3-aminopyrrolidine-containing template leading to the identification of GI-restricted agonist 19 (GSK3004774).
Assuntos
Receptores de Detecção de Cálcio/agonistas , Animais , Cálcio/metabolismo , Permeabilidade da Membrana Celular/efeitos dos fármacos , Cães , Trato Gastrointestinal/metabolismo , Células HEK293 , Humanos , Células Madin Darby de Rim Canino , Pirrolidinas/química , Pirrolidinas/metabolismo , Pirrolidinas/farmacologia , Receptores de Detecção de Cálcio/genética , Receptores de Detecção de Cálcio/metabolismo , Relação Estrutura-AtividadeRESUMO
The long chain free fatty acid receptor 4 (FFA4/GPR120) has recently been recognized as lipid sensor playing important roles in nutrient sensing and inflammation and thus holds potential as a therapeutic target for type 2 diabetes and metabolic syndrome. To explore the effects of stimulating this receptor in animal models of metabolic disease, we initiated work to identify agonists with appropriate pharmacokinetic properties to support progression into in vivo studies. Extensive SAR studies of a series of phenylpropanoic acids led to the identification of compound 29, a FFA4 agonist which lowers plasma glucose in two preclinical models of type 2 diabetes.
Assuntos
Fenilpropionatos/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Animais , Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Modelos Animais de Doenças , Humanos , Masculino , Camundongos , Fenilpropionatos/química , Fenilpropionatos/farmacocinética , Fenilpropionatos/uso terapêutico , Ligação Proteica/efeitos dos fármacos , Ratos , Receptores Acoplados a Proteínas G/metabolismo , Relação Estrutura-AtividadeRESUMO
The identification of a low-permeability scavenger receptor BI (SR-BI) inhibitor starting from the ITX-5061 template is described. Structure-activity and structure-permeability relationships were assessed for analogs leading to the identification of compound 8 as a potent and nonabsorbable SR-BI inhibitor.
Assuntos
Fenilenodiaminas/farmacologia , Receptores Depuradores Classe B/antagonistas & inibidores , Sulfonamidas/farmacologia , Animais , Cães , Relação Dose-Resposta a Droga , Humanos , Células Madin Darby de Rim Canino , Estrutura Molecular , Especificidade de Órgãos , Fenilenodiaminas/administração & dosagem , Fenilenodiaminas/química , Ratos , Relação Estrutura-Atividade , Sulfonamidas/administração & dosagem , Sulfonamidas/químicaRESUMO
The exploration of a diarylsulfonamide series of free fatty acid receptor 4 (FFA4/GPR120) agonists is described. This work led to the identification of selective FFA4 agonist 8 (GSK137647A) and selective FFA4 antagonist 39. The in vitro profile of compounds 8 and 39 is presented herein.
Assuntos
Receptores Acoplados a Proteínas G/agonistas , Sulfonamidas/farmacologia , Animais , Linhagem Celular , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Insulina/agonistas , Camundongos , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/químicaRESUMO
A series of 3-aryl-4-isoxazolecarboxamides identified from a high-throughput screening campaign as novel, potent small molecule agonists of the human TGR5 G-protein coupled receptor is described. Subsequent optimization resulted in the rapid identification of potent exemplars 6 and 7 which demonstrated improved GLP-1 secretion in vivo via an intracolonic dose coadministered with glucose challenge in a canine model. These novel TGR5 receptor agonists are potentially useful therapeutics for metabolic disorders such as type II diabetes and its associated complications.
Assuntos
Isoxazóis/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Amidas/química , Amidas/farmacocinética , Amidas/farmacologia , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Modelos Animais de Doenças , Cães , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Glucose/administração & dosagem , Humanos , Isoxazóis/química , Isoxazóis/farmacocinética , RatosRESUMO
The melanophore bioassay is a robust, sensitive, and versatile procedure for screening G protein-coupled receptors in a variety of formats. Because melanophores contain a wide variety of G proteins, they can be employed as a sensitive, real-time response system for studying transfected receptors and for defining equilibria for drug effects. This assay can be run in 96-well microtiter plates or in open-lawn 1536 format, and can yield conventional agonist-antagonist as well as constitutive assays.