化学
效力
兴奋剂
药理学
部分激动剂
代谢稳定性
药效学
药代动力学
受体
立体化学
体外
生物化学
医学
作者
Wei Meng,Zulan Pi,Robert Brigance,Karen A. Rossi,William A. Schumacher,Jeffrey S. Bostwick,Peter S. Gargalovic,Joelle M. Onorato,Chiuwa E. Luk,Claudia Generaux,Tao Wang,Ruth R. Wexler,Heather J. Finlay
标识
DOI:10.1021/acs.jmedchem.1c01504
摘要
This paper describes our continued efforts in the area of small-molecule apelin receptor agonists. Recently disclosed compound 2 showed an acceptable metabolic stability but demonstrated monodemethylation of the dimethoxyphenyl group to generate atropisomer metabolites in vitro. In this article, we extended the structure-activity relationship at the C2 position that led to the identification of potent pyrazole analogues with excellent metabolic stability. Due to the increased polarity at C2, the permeability for these compounds decreased. Further adjustment of the polarity by replacing the N1 2,6-dimethoxyphenyl group with a 2,6-diethylphenyl group and reoptimization for the potency of the C5 pyrroloamides resulted in potent compounds with improved permeability. Compound 21 displayed excellent pharmacokinetic profiles in rat, monkey, and dog models and robust pharmacodynamic efficacy in the rodent heart failure model. Compound 21 also showed an acceptable safety profile in preclinical toxicology studies and was selected as a backup development candidate for the program.
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