Journal
ARCHIV DER PHARMAZIE
Volume 354, Issue 4, Pages -Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/ardp.202000275
Keywords
FFA1 receptor; free fatty acids; glucose‐ stimulated insulin secretion; GPR40; heterocyclic periphery; hyperglycemia; type 2 diabetes mellitus
Funding
- Russian Foundation for Basic Research [19-33-90169]
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Three types of heterocyclic moieties were investigated as potential periphery motifs for fasiglifam, with compound 16a identified as the lead compound for further development based on its promising potential in cellular efficacy tests.
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.
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