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

作者：Li Peng^*; Zhang Qiang; Robichaud Albert J; Lee Taekyu; Tomesch John; Yao Wei; Beard J David; Snyder Gretchen L; Zhu Hongwen; Peng Youyi; Hendrick Joseph P; Vanover Kimberly E; Davis Robert E; Mates Sharon; Wennogle Lawrence P

来源：Journal of Medicinal Chemistry, 2014, 57(6): 2670-2682.

DOI：10.1021/jm401958n

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.

• 出版日期2014-3-27