posted on 2021-12-02, 21:07authored byWei Meng, Zulan Pi, Robert Brigance, Karen A. Rossi, William A. Schumacher, Jeffrey S. Bostwick, Peter S. Gargalovic, Joelle M. Onorato, Chiuwa E. Luk, Claudia N. Generaux, Tao Wang, Ruth R. Wexler, Heather J. Finlay
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.