Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 5 de 5
Filtrar
Mais filtros








Base de dados
Intervalo de ano de publicação
1.
Nat Commun ; 14(1): 5938, 2023 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-37741852

RESUMO

GPR61 is an orphan GPCR related to biogenic amine receptors. Its association with phenotypes relating to appetite makes it of interest as a druggable target to treat disorders of metabolism and body weight, such as obesity and cachexia. To date, the lack of structural information or a known biological ligand or tool compound has hindered comprehensive efforts to study GPR61 structure and function. Here, we report a structural characterization of GPR61, in both its active-like complex with heterotrimeric G protein and in its inactive state. Moreover, we report the discovery of a potent and selective small-molecule inverse agonist against GPR61 and structural elucidation of its allosteric binding site and mode of action. These findings offer mechanistic insights into an orphan GPCR while providing both a structural framework and tool compound to support further studies of GPR61 function and modulation.


Assuntos
Agonismo Inverso de Drogas , Proteínas de Ligação ao GTP , Receptores Acoplados a Proteínas G , Sítio Alostérico , Apetite , Sítios de Ligação , Proteínas de Ligação ao GTP/metabolismo , Humanos , Receptores Acoplados a Proteínas G/agonistas
2.
J Med Chem ; 66(5): 3195-3211, 2023 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-36802610

RESUMO

The melanocortin-4 receptor (MC4R) is a centrally expressed, class A GPCR that plays a key role in the regulation of appetite and food intake. Deficiencies in MC4R signaling result in hyperphagia and increased body mass in humans. Antagonism of MC4R signaling has the potential to mitigate decreased appetite and body weight loss in the setting of anorexia or cachexia due to underlying disease. Herein, we report on the identification of a series of orally bioavailable, small-molecule MC4R antagonists using a focused hit identification effort and the optimization of these antagonists to provide clinical candidate 23. Introduction of a spirocyclic conformational constraint allowed for simultaneous optimization of MC4R potency and ADME attributes while avoiding the production of hERG active metabolites observed in early series leads. Compound 23 is a potent and selective MC4R antagonist with robust efficacy in an aged rat model of cachexia and has progressed into clinical trials.


Assuntos
Apetite , Receptor Tipo 4 de Melanocortina , Ratos , Humanos , Animais , Caquexia/tratamento farmacológico , Anorexia/tratamento farmacológico , Conformação Molecular
4.
Bioorg Med Chem Lett ; 20(1): 266-71, 2010 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-19914063

RESUMO

Based on our original pyrazine hit, CP-0809101, novel conformationally-restricted 5HT2c receptor agonists with 2-piperazin-azaindane scaffold were designed. Synthesis and structure-activity relationship (SAR) studies are described with emphasis on optimization of the selectivity against 5HT2a and 5HT2b receptors with excellent 2c potency. Orally-active and selective compounds were identified with dose-responsive in vivo efficacy in our pre-clinical food intake model.


Assuntos
Fármacos Antiobesidade/síntese química , Compostos Aza/síntese química , Agonistas do Receptor 5-HT2 de Serotonina , Agonistas do Receptor de Serotonina/síntese química , Administração Oral , Animais , Fármacos Antiobesidade/química , Fármacos Antiobesidade/farmacologia , Compostos Aza/química , Compostos Aza/farmacologia , Cães , Desenho de Fármacos , Haplorrinos , Humanos , Obesidade/tratamento farmacológico , Ratos , Receptor 5-HT2C de Serotonina/metabolismo , Agonistas do Receptor de Serotonina/química , Agonistas do Receptor de Serotonina/farmacologia
5.
Eur J Pharmacol ; 451(1): 37-41, 2002 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-12223226

RESUMO

We evaluated the in vitro pharmacological profile of a novel, potent and highly selective Na(+)/H(+) exchanger-1 (NHE-1) inhibitor, [1-(Quinolin-5-yl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine hydrochloride monohydrate (zoniporide or CP-597,396). The potency and selectivity of zoniporide were determined via inhibition of 22Na(+) uptake by PS-120 fibroblast cell lines overexpressing human NHE-1, -2 or rat NHE-3. Additionally, potency for endogenous NHE-1 was confirmed via ex vivo human platelet swelling assay (PSA), in which platelet swelling was induced by exposure to sodium propionate. The pharmacological profile of zoniporide was compared with that of eniporide and cariporide. Zoniporide inhibited 22Na(+) uptake in fibroblasts expressing human NHE-1 in a concentration-dependent manner (IC(50) = 14 nM) and was highly selective (157-fold and 15,700-fold vs. human NHE-2 and rat NHE-3, respectively). Zoniporide was 1.64- to 2.6-fold more potent at human NHE-1 than either eniporide or cariporide (IC(50) = 23 and 36 nM, respectively). Zoniporide was also more selective at inhibiting human NHE-1 vs. human NHE-2 than either eniporide or cariporide (157-fold selective compared with 27- and 49-fold, respectively). All three compounds inhibited human platelet swelling with IC(50) values in low nanomolar range. From these results, we conclude that zoniporide represents a novel, potent and highly selective NHE-1 inhibitor.


Assuntos
Guanidinas/farmacologia , Pirazóis/farmacologia , Trocadores de Sódio-Hidrogênio/antagonistas & inibidores , Células Cultivadas , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Sódio/metabolismo , Sulfonas/farmacologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA