RESUMEN
A set of 1,3,4-thiadiazole-2-carboxamides bearing a substituted biphenyl in the amide portion was synthesised and tested for agonistic activity towards free fatty acid receptor 1 (FFA1). The observed activity trends were impossible to rationalised based solely on the docking energy scores of Glide SP. On the contrary, when the phospholipid cell membrane bilayer was reconstructed around FFA1, it became apparent that inactive compounds displayed significant strained contacts with the membrane while for active compounds the strain was noticeably lower. These findings justify using the improved docking protocol for modelling GPCR-ligand interactions which uses the crystal structure of the receptor and a reconstructed portion of a cell membrane.
Asunto(s)
Hidrazinas/farmacología , Receptores Acoplados a Proteínas G/agonistas , Bibliotecas de Moléculas Pequeñas/farmacología , Membrana Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Hidrazinas/síntesis química , Hidrazinas/química , Ligandos , Estructura Molecular , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/química , Relación Estructura-ActividadRESUMEN
Three types of heterocyclic moieties-piperidines fused to a heteroaromatic moiety-were explored as potential periphery motifs for the pharmacophoric core of fasiglifam (TAK-875), with fasiglifam being the most advanced agonist of free fatty acid receptor 1, a promising target for therapeutic intervention in type 2 diabetes. Several observed structure-activity relationship trends were corroborated by in silico docking results. Balanced selection based on potency and Caco-2 permeability advanced six compounds to cellular efficacy tests (glucose-stimulated insulin secretion in rat insulinoma INS1E cells). This led to the nomination of compound 16a (LK1408, 3-[4-({4-[(3-{[(2-fluorobenzyl)oxy]methyl}-1-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)methyl]benzyl}oxy)phenyl]propanoic acid hydrochloride) as the lead for further development.
Asunto(s)
Benzofuranos/farmacología , Compuestos Heterocíclicos/farmacología , Piperidinas/farmacología , Receptores Acoplados a Proteínas G/agonistas , Sulfonas/farmacología , Benzofuranos/síntesis química , Benzofuranos/química , Células CACO-2 , Relación Dosis-Respuesta a Droga , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/química , Humanos , Estructura Molecular , Piperidinas/síntesis química , Piperidinas/química , Relación Estructura-Actividad , Sulfonas/síntesis química , Sulfonas/químicaRESUMEN
A three-component reaction involving in situ generation of propargylureas and subsequent Zn(OTf)2-mediated cyclocondensation with a primary amine yielded trisubstituted 2-aminoimidazoles. These findings are in contrast to the previously reported base-promoted unimolecular cyclization of propargylureas (leading to 2-imidazolones) and extend the range of Lewis acid-catalyzed azole syntheses based on N-carbonyl propargylamines.
RESUMEN
An earlier reported series of 1,2,4-thiadiazole-based agonists of FFA1 (GPR40) was evolved into two structurally distinct series of compounds. One of the series (structurally related to known FFA1 agonist GW9508) displayed low micromolar potency while the other (representing a truncated version of the earlier reported potent FFA1 agonists) was, surprisingly, found to be devoid of agonist potency. In silico docking of representative compounds into the crystal structure of FFA1 revealed possible structural grounds for the observed SAR.