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Identification of a Hydroxypyrimidinone Compound (21) as a Potent APJ Receptor Agonist for the Potential Treatment of Heart Failure
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-12-02 , DOI: 10.1021/acs.jmedchem.1c01504
Wei Meng 1 , Zulan Pi 1 , Robert Brigance 1 , Karen A Rossi 2 , William A Schumacher 3 , Jeffrey S Bostwick 3 , Peter S Gargalovic 3 , Joelle M Onorato 4 , Chiuwa E Luk 4 , Claudia N Generaux 4 , Tao Wang 5 , Ruth R Wexler 1 , Heather J Finlay 1
Affiliation  

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.

中文翻译:

鉴定羟基嘧啶酮化合物 (21) 作为潜在治疗心力衰竭的有效 APJ 受体激动剂

本文描述了我们在小分子 apelin 受体激动剂领域的持续努力。最近公开的化合物2显示出可接受的代谢稳定性,但在体外证明了二甲氧基苯基的单去甲基化以产生阻转异构体代谢物。在本文中,我们扩展了 C2 位的构效关系,从而鉴定出具有优异代谢稳定性的有效吡唑类似物。由于 C2 处的极性增加,这些化合物的渗透性降低。通过用 2,6-二乙基苯基取代 N1 2,6-二甲氧基苯基进一步调整极性,并重新优化 C5 吡咯酰胺的效力,从而产生具有改善渗透性的有效化合物。化合物21在大鼠、猴子和狗模型中显示出优异的药代动力学特征,在啮齿动物心力衰竭模型中显示出强大的药效学功效。化合物21在临床前毒理学研究中也显示出可接受的安全性,并被选为该计划的备用开发候选者。
更新日期:2021-12-23
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