RESUMO
High-throughput screening of a subset of the J&J compound library containing the carboxylic acid functional group uncovered a bromophenyl derivative as a moderate potent GPR40 agonist. Chemical elaboration of this bromophenyl led to the discovery of a novel series of GPR40 agonists with submicromolar potency. Among them, 22 and 24 behaved as full agonists when compared to the endogenous GPR40 ligand linolenic acid in a functional Ca+2 flux assay in HEK cells expressing GPR40 receptor. Several GPR40 agonists have also demonstrated the ability to induce glucose-mediated insulin secretion in the mouse MIN6 pancreatic beta-cell line. Our data supports the hypothesis that GPR40 may play an important role in fatty acid-mediated glucose-dependent insulin secretion. Compound 22 exhibited good pharmacokinetic profile in rat and may serve as a good candidate for in vivo study and may help to determine if GPR40 agonists would be beneficial in the treatment of type II diabetes.
Assuntos
Fenilpropionatos/síntese química , Propionatos/síntese química , Receptores Acoplados a Proteínas G/agonistas , Animais , Disponibilidade Biológica , Cálcio/metabolismo , Linhagem Celular , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Insulina/metabolismo , Secreção de Insulina , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Camundongos , Fenilpropionatos/farmacocinética , Fenilpropionatos/farmacologia , Propionatos/farmacocinética , Propionatos/farmacologia , Ratos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Reduction of the quinoline ring in an alpha(v)beta(3) antagonist yielded a 1,2,3,4-tetrahydro derivative as two diastereomers, the four isomers of which were separated by sequential chiral HPLC. Two isomers had significant alpha(V)beta(3) antagonist activity with improved oral bioavailability, relative to the corresponding quinoline derivative.
Assuntos
Integrina alfaVbeta3/antagonistas & inibidores , Integrina alfaVbeta3/metabolismo , Quinolinas/química , Quinolinas/metabolismo , Administração Oral , Animais , Disponibilidade Biológica , Humanos , Quinolinas/administração & dosagem , RatosRESUMO
The synthesis and SAR of a new class of piperidine-based alphavbeta3/alphavbeta5 integrin antagonists is described. Replacement of an amide bond in a prototype isonipecotamide by a C-C isostere, and adjustment of the spacer length between the carboxylic acid and basic moieties, led to low nanomolar antagonists of alphavbeta3 and/or alphavbeta5 integrins with excellent selectivity versus alpha(IIb)beta3.