Synthesis and biological investigation of tetrahydropyridopyrimidinone derivatives as potential multireceptor atypical antipsychotics.

Abstract

In the present study, a series of tetrahydropyridopyrimidinone derivatives, possessing potent dopamine D2, serotonin 5-HT1A and 5-HT2A receptors properties, was synthesized and evaluated as potential antipsychotics. Among them, 3-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (10d) held the best pharmacological profile. It not only exhibited potent and balanced activities for D2, 5-HT1A, and 5-HT2A receptors, but was also endowed with low activities for α1A, 5-HT2C, H1 receptors and hERG channels, suggesting a low propensity for inducing orthostatic hypotension, weight gain and QT prolongation. In animal models, compound 10d reduced phencyclidine-induced hyperactivity with a high threshold for catalepsy induction. On the basis of its robust in vitro potency and in vivo efficacy in preclinical models of schizophrenia, coupled with a good pharmacokinetic profile, 10d was selected as a candidate for further development.

• Authors: Hainimu Xiamuxi, Zhen Wang, Jianfeng Li, Yu Wang, Chunhui Wu, Feipu Yang, Xiangrui Jiang, Yongjian Liu, Qingjie Zhao, Weiming Chen, Jian Zhang, Yuanchao Xie, Tianwen Hu, Mingshuo Xu, Shuang Guo, Haji Akber Aisa, Yang He, Jingshan Shen
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 25 Issue 17 Pg. 4904-4916 (09 01 2017) ISSN: 1464-3391 [Electronic] England
• PMID: 28774576 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 Elsevier Ltd. All rights reserved.

Chemical References

• Antipsychotic Agents
• Pyrimidinones
• Receptor, Serotonin, 5-HT2A
• Receptors, Dopamine D2
• Receptor, Serotonin, 5-HT1A

Topics

• Animals
• Antipsychotic Agents (chemical synthesis, pharmacology, therapeutic use)
• Behavior, Animal (drug effects)
• Catalepsy (chemically induced, drug therapy, pathology)
• Disease Models, Animal
• Dogs
• Half-Life
• Humans
• Inhibitory Concentration 50
• Mice
• Microsomes, Liver (metabolism)
• Pyrimidinones (chemistry, pharmacology, therapeutic use)
• Rats
• Rats, Sprague-Dawley
• Receptor, Serotonin, 5-HT1A (chemistry, metabolism)
• Receptor, Serotonin, 5-HT2A (chemistry, metabolism)
• Receptors, Dopamine D2 (chemistry, metabolism)
• Structure-Activity Relationship