RESUMO
The discovery and optimization of a novel series of GPR142 agonists are described. These led to the identification of compound 21 (LY3325656), which demonstrated anti-diabetic benefits in pre-clinical studies and ADME/PK properties suitable for human dosing. Compound 21 is the first GPR142 agonist molecule advancing to phase 1 clinic trials for the treatment of Type 2 diabetes.
Assuntos
Benzamidas/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Receptores Acoplados a Proteínas G/agonistas , Triazóis/uso terapêutico , Animais , Benzamidas/síntese química , Benzamidas/farmacocinética , Cães , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Técnicas de Inativação de Genes , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/farmacocinética , Camundongos Knockout , Estrutura Molecular , Ratos , Receptores Acoplados a Proteínas G/genética , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/farmacocinéticaRESUMO
A new chemotype of ghrelin inverse agonists was discovered through chimeric design based on molecular scaffolds known as growth-hormone secretagogue receptor (GHSR) modulators but with divergent pharmacodynamic and pharmacokinetic properties. The structure-activities/properties exploration led to compound 47, which displayed potent human GHSR antagonism and inverse agonism in cellular assays (IC50 = 68 nM, EC50 = 29 nM), moderate oral bioavailability, and notable brain penetration in rat ( F = 27%, B/ P ratio = 1.9). First in vivo studies demonstrated effective reduction of food intake after oral or parenteral administration to mouse (78% at 1 h and 38% at 8 h, respectively). Further preclinical studies are needed to evaluate the most suited mode of administration with the aim of promoting a first central-acting ghrelin inverse agonist molecule to development, which would represent a significant step toward therapeutic agents to treat metabolic disorders related to obesity, such as type 2 diabetes mellitus.
Assuntos
Alcinos/síntese química , Ciclopropanos/síntese química , Doenças Metabólicas/tratamento farmacológico , Obesidade/complicações , Piperidinas/síntese química , Receptores de Grelina/agonistas , Administração Oral , Alcinos/administração & dosagem , Alcinos/farmacologia , Animais , Disponibilidade Biológica , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Ciclopropanos/administração & dosagem , Ciclopropanos/farmacologia , Cães , Canal de Potássio ERG1/antagonistas & inibidores , Ingestão de Alimentos/efeitos dos fármacos , Humanos , Masculino , Camundongos Endogâmicos C57BL , Microssomos Hepáticos/efeitos dos fármacos , Simulação de Acoplamento Molecular , Obesidade/metabolismo , Piperidinas/administração & dosagem , Piperidinas/farmacologia , Ratos , Receptores de Grelina/antagonistas & inibidores , Receptores de Grelina/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
There is an increasing amount of evidence to support that activation of the metabotropic glutamate receptor 4 (mGlu4 receptor), either with an orthosteric agonist or a positive allosteric modulator (PAM), provides impactful interventions in diseases such as Parkinson's disease, anxiety, and pain. mGlu4 PAMs may have several advantages over mGlu4 agonists for a number of reasons. As part of our efforts in identifying therapeutics for central nervous system (CNS) diseases such as Parkinson's disease, we have been focusing on metabotropic glutamate receptors. Herein we report our studies with a series of tricyclic thiazolopyrazoles as mGlu4 PAMs.
