Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 56, Issue 11, Pages 4671-4690Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm400408r
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Funding
- National Science and Technology Major Project Key New Drug Creation and Manufacturing Program [2012ZX09103-101-010]
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The discovery and synthesis of potential and novel antipsychotic coumarin derivatives, associated with potent dopamine 132, D3, and serotonin S-HT1A and S-HT2A, receptor properties, are the focus of the present article. The most-promising derivative was 7-(4-(4-(6-fluorobenzo[d]-isoxazol-3-yl)-piperidin-1-yl)butoxy)-4-methyl-8-chloro-2H- chromen-2-one (17m). This derivative possesses unique pharmacological features, including high affinity for dopamine D-2 and D-3 and serotonin S-HT1A and 5-HT2A receptors. Moreover, it possesses low affinity for S-HT2C and H-1 receptors (to reduce the risk of obesity associated with chronic treatment) and hERG channels (to reduce the incidence of torsade des pointes). In animal models, compound 17m inhibited apomorphine-induced climbing behavior, MK-801-induced hyperactivity, and the conditioned avoidance response without observable catalepsy at the highest dose tested. Further, fewer preclinical adverse events were noted with 17m compared with risperidone in assays that measured prolactin secretion and weight gain. Acceptable pharmacokinetic properties were also noted with 17m. Taken together, 17m may constitute a novel class of drugs for the treatment of schizophrenia.
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