Characteristics of metabolic stability and the cell permeability of 2‐pyrimidinyl‐piperazinyl‐alkyl derivatives of 1H‐imidazo[2,1‐f]purine‐2,4(3H,8H)‐dione with antidepressant‐ and anxiolytic‐like activities

Abstract

A series of 2‐pyrimidinyl‐piperazinyl‐alkyl derivatives of 1H‐imidazo[2,1‐f]purine‐2,4(3H,8H)‐dione has been synthesized in an attempt to discover a new class of psychotropic agents. Compounds were evaluated for their in vitro affinity for serotonin 5‐HT1A, 5‐HT7, and phosphodiesterases PDE4 and PDE10. The most potent compound 2‐pyrimidinyl‐1‐piperazinyl‐butyl‐imidazo[2,1‐f]purine‐2,4‐dione (4b) behaved as strong and selective antagonist of 5‐HT1A. Molecular modeling studies revealed differences in binding mode between compound 4b and buspirone, which might reflect variation of the ligands’ affinity and potency in the 5‐HT1A receptor. Compound 4b in silico models demonstrated drug‐likeness properties and, contrary to buspirone, showed a metabolic stability in mouse liver microsomes system. Experimentally obtained value of apparent permeability coefficient Papp for 4b in parallel artificial permeability assay indicates the possibility of binding weakly to plasma proteins and high intestinal absorption fraction. Evaluation of the antidepressant‐ and anxiolytic‐like activities of 4b revealed both activities at the same dose of 1.25 mg/kg and seemed to be specific. The antidepressant and/or anxiolytic properties of 4b may be related to its first‐pass effect.

Piperazine, a Key Substructure for Antidepressants: Its Role in Developments and Structure‐Activity Relationships

“…The same research group synthesized a series of novel 2‐pyrimidynyl‐piperazinyl‐alkyl derivatives of 1 H ‐imidazo[2,1 ‐f ]purine‐2,4(3 H ,8 H )‐dione as CNS active agents [65] . Among the synthesized compounds, most of them showed a potent affinity towards 5HT 1 ARs with K i ranging from 2.2 to 20 nM.…”

A new FGFR inhibitor disrupts the TGF‐β1‐induced fibrotic process

“…In addition, IM‐412 inhibited invasion and migration of MDA‐MB‐231 breast cancer cells by suppression of epithelial‐to‐mesenchymal transition (EMT) process . The pharmacological activity of the imidazole moiety has been demonstrated in many medications, including anti‐infective, anticancer, antiviral, antitubercular, anticonvulsant and antidepressant activity and imidazo[2,1‐ f ]purine‐2,4‐dione derivatives exhibited adenosine receptor antagonist and potent activator of serotonin transporter . However, molecular target of imidazopurine compounds and their roles in fibrotic process were not clearly elucidated.…”

“…14 The pharmacological activity of the imidazole moiety has been demonstrated in many medications, including anti-infective, anticancer, antiviral, antitubercular, anticonvulsant and antidepressant activity 15 and imidazo[2,1-f]purine-2,4-dione derivatives exhibited adenosine receptor antagonist 16 and potent activator of serotonin transporter. 17,18 However, molecular target of imidazopurine compounds and their roles in fibrotic process were not clearly elucidated. Here, we investigated whether another analogue of IM-412, 3-(2-chloro-6-fluorobenzyl)-1,6,7-trimethyl-1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione (IM-1918), inhibits the TGF-β-mediated fibrotic process and also evaluated the underlying mechanisms.…”