Discovery of a Tetracyclic Quinoxaline Derivative as a Potent and Orally Active Multifunctional Drug Candidate for the Treatment of Neuropsychiatric and Neurological Disorders

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• 作者：Peng Li ; Qiang Zhang ; Albert J. Robichaud ; Taekyu Lee ; John Tomesch ; Wei Yao ; J. David Beard ; Gretchen L. Snyder ; Hongwen Zhu ; Youyi Peng ; Joseph P. Hendrick ; Kimberly E. Vanover ; Robert E. Davis ; Sharon Mates ; Lawrence P. Wennogle
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：March 27, 2014
• 年：2014
• 卷：57
• 期：6
• 页码：2670-2682
• 全文大小：452K
• 年卷期：v.57,no.6(March 27, 2014)
• ISSN：1520-4804

文摘

We report the synthesis and structure鈥揳ctivity relationships of a class of tetracyclic butyrophenones that exhibit potent binding affinities to serotonin 5-HT_2A and dopamine D₂ receptors. This work has led to the discovery of 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3鈥?4鈥?4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-1-(4-fluorophenyl)-butan-1-one 4-methylbenzenesulfonate (ITI-007), which is a potent 5-HT_2A antagonist, postsynaptic D₂ antagonist, and inhibitor of serotonin transporter. This multifunctional drug candidate is orally bioavailable and exhibits good antipsychotic efficacy in vivo. Currently, this investigational new drug is under clinical development for the treatment of neuropsychiatric and neurological disorders.