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

被引：69

作者：

Li, Peng ^{[1
]}

Zhang, Qiang ^{[1
]}

Robichaud, Albert J. ^{[2
]}

Lee, Taekyu ^{[2
]}

Tomesch, John ^{[1
]}

Yao, Wei ^{[1
]}

Beard, J. David ^{[1
]}

Snyder, Gretchen L. ^{[1
]}

Zhu, Hongwen ^{[1
]}

Peng, Youyi ^{[1
]}

Hendrick, Joseph P. ^{[1
]}

Vanover, Kimberly E. ^{[1
]}

Davis, Robert E. ^{[3
]}

Mates, Sharon ^{[1
]}

Wennogle, Lawrence P. ^{[1
]}

机构：

[1] Intracellular Therapies Inc, New York, NY 10032 USA

[2] Bristol Myers Squibb Res & Dev, Med Chem, Princeton, NJ 08543 USA

[3] 3D Pharmaceut Consultants Inc, San Diego, CA 92130 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2014年 / 57卷 / 06期

关键词：

5-HT2C RECEPTORS; NEUROLEPTICS; ANTAGONISTS; AFFINITIES; RATS;

D O I：

10.1021/jm401958n

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We report the synthesis and structure-activity relationships of a class of tetracyclic butyrophenones that exhibit potent binding affinities to serotonin 5-HT2A and dopamine D-2 receptors. This work has led to the discovery of 44(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3',4':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-HT2A antagonist, postsynaptic D-2 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.

引用

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页码：2670 / 2682

页数：13

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