Exploration of the nitrogen heterocyclic periphery around the core of the advanced FFA1 agonist fasiglifam (TAK-875).
Alexey LukinAnna BakholdinaNikolay ZhuriloOleksandra OnopchenkoElena ZhuravelSergey ZozulyaMaxim A GureevAlexander SafryginMikhail Yu KrasavinPublished in: Archiv der Pharmazie (2020)
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.
Keyphrases
- molecular dynamics simulations
- molecular docking
- type diabetes
- structure activity relationship
- fatty acid
- induced apoptosis
- randomized controlled trial
- cell cycle arrest
- oxidative stress
- cardiovascular disease
- endothelial cells
- climate change
- metabolic syndrome
- signaling pathway
- glycemic control
- cell proliferation
- small molecule
- pi k akt