PDE10A型
化学
精神分裂症(面向对象编程)
合理设计
嘧啶
调节器
药代动力学
药理学
失调家庭
磷酸二酯酶
立体化学
生物化学
心理学
酶
精神科
基因
纳米技术
医学
材料科学
作者
M. E. Layton,Jeffrey C. Kern,Timothy J. Hartingh,William D. Shipe,Izzat T. Raheem,Monika Kandebo,Robert P. Hayes,Sarah L. Huszar,Donnie Eddins,Bennett Ma,Joy Fuerst,Gordon K. Wollenberg,Jing Li,Jeff Fritzen,Georgia B. McGaughey,Jason M. Uslaner,Sean M. Smith,Paul J. Coleman,Christopher D. Cox
标识
DOI:10.1021/acs.jmedchem.2c01521
摘要
PDE10A is an important regulator of striatal signaling that, when inhibited, can normalize dysfunctional activity. Given the involvement of dysfunctional striatal activity with schizophrenia, PDE10A inhibition represents a potentially novel means for its treatment. With the goal of developing PDE10A inhibitors, early optimization of a fragment hit through rational design led to a series of potent pyrimidine PDE10A inhibitors that required further improvements in physicochemical properties, off-target activities, and pharmacokinetics. Herein we describe the discovery of an isomeric pyrimidine series that addresses the liabilities seen with earlier compounds and resulted in the invention of compound 18 (MK-8189), which is currently in Phase 2b clinical development for the treatment of schizophrenia.
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