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.
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.
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