Exploration of the nitrogen heterocyclic periphery around the core of the advanced FFA1 agonist fasiglifam (TAK‐875)

Abstract

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.

5-Nitrofuran-Tagged Oxazolyl Pyrazolopiperidines: Synthesis and Activity against ESKAPE Pathogens

“…Based on recent studies and previously acquired data from sources [ 7 , 8 , 9 ], we can now suggest pharmacophore structures derived from a combination of molecular fragments with varying antibiotic properties. Compounds derived from tetrahydropyrazolopyridine (THPP) have demonstrated a very wide spectrum of biological activity such as different enzyme inhibition [ 10 , 11 , 12 , 13 ], antiviral [ 14 , 15 ], and antimicrobial [ 16 , 17 , 18 ] activity. This molecule presents three potential sites for modification, offering a tremendous opportunity for innovative design.…”

“…activity such as different enzyme inhibition [10][11][12][13], antiviral [14,15], and antim [16][17][18] activity. This molecule presents three potential sites for modification, of tremendous opportunity for innovative design.…”

5-Nitrofuran-Tagged Oxazolyl Pyrazolopiperidines: Synthesis and Activity against ESKAPE Pathogens

“…Based on recent studies and previously acquired data from sources [7][8][9], we can now suggest pharmacophore structures derived from a combination of molecular fragments with varying antibiotic properties. Compounds derived from tetrahydropyrazolopyridine (THPP) have demonstrated a very wide spectrum of biological activity such as different enzyme inhibition [10][11][12][13], antiviral [14,15], and antimicrobial [16][17][18] activity. This molecule presents three potential sites for modification, Molecules 2023, 28, 6491 2 of 14 offering a tremendous opportunity for innovative design.…”