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Bioorg Med Chem ; 26(18): 5169-5180, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30253886

RESUMO

Free fatty acid-2 (FFA2) receptor is a G-protein coupled receptor of interest in the development of therapeutics in metabolic and inflammatory disease areas. The discovery and optimization of an N-thiazolylamide carboxylic acid FFA2 agonist scaffold is described. Dual key objectives were to i) evaluate the potential of this scaffold for lead optimization in particular with respect to safety de-risking physicochemical properties, i.e. lipophilicity and aromatic content, and ii) to demonstrate the utility of selected lead analogues from this scaffold in a pertinent in vivo model such as oral glucose tolerance test (OGTT). As such, a concomitant improvement in bioactivity together with lipophilic ligand efficiency (LLE) and fraction sp3 content (Fsp3) parameters guided these efforts. Compound 10 was advanced into studies in mice on the basis of its optimized profile vs initial lead 1 (ΔLLE = 0.3, ΔFsp3 = 0.24). Although active in OGTT, 10 also displayed similar activity in the FFA2-knockout mice. Given this off-target OGTT effect, we discontinued development of this FFA2 agonist scaffold.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Modelos Animais de Doenças , Descoberta de Drogas , Receptores de Superfície Celular/agonistas , Tiazóis/farmacologia , Animais , Relação Dose-Resposta a Droga , Humanos , Camundongos , Camundongos Knockout , Estrutura Molecular , Ratos , Receptores de Superfície Celular/deficiência , Receptores de Superfície Celular/metabolismo , Relação Estrutura-Atividade , Tiazóis/química
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