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Exploration of the nitrogen heterocyclic periphery around the core of the advanced FFA1 agonist fasiglifam (TAK‐875)
Author(s) -
Lukin Alexey,
Bakholdina Anna,
Zhurilo Nikolay,
Onopchenko Oleksandra,
Zhuravel Elena,
Zozulya Sergey,
Gureev Maxim,
Safrygin Alexander,
Krasavin Mikhail
Publication year - 2021
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.202000275
Subject(s) - chemistry , propanoic acid , moiety , agonist , stereochemistry , in silico , docking (animal) , receptor , combinatorial chemistry , biochemistry , medicine , nursing , gene
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‐5 H ‐pyrazolo[4,3‐ c ]pyridin‐5‐yl)methyl]benzyl}oxy)phenyl]propanoic acid hydrochloride) as the lead for further development.