posted on 2022-12-10, 13:03authored byJian Zhao, Shimiao Wang, Stacy Markison, Sun Hee Kim, Sangdon Han, Mi Chen, Ana Karin Kusnetzow, Elizabeth Rico-Bautista, Michael Johns, Rosa Luo, R. Scott Struthers, Ajay Madan, Yunfei Zhu, Stephen F. Betz
The discovery of a novel 4-(4-aminopiperidinyl)-3,6-diarylquinoline
series of potent SST2 agonists is described. This class of molecules
exhibit excellent selectivity over SST1, SST3, SST4, and SST5 receptors.
The compound 3-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-2-hydroxybenzonitrile
(22, paltusotine, formerly known as CRN00808) showed
no direct inhibition of major cytochrome P450 enzymes or the hERG
ion channel and had sufficient exposure in rats and excellent exposure
in dogs upon oral dosing. In pharmacodynamic studies, compound 22 dose-dependently suppressed growth hormone (GH) secretion
induced by an exogenous growth-hormone-releasing hormone (GHRH) challenge
in both male and female rats following a single oral dose and suppressed
IGF-1 levels with repeated oral administration in both rats and dogs.
To the best of our knowledge, compound 22 is the first
non-peptide SST2 agonist to advance to human clinical trials and is
currently in Phase 3 trials in acromegaly patients and a Phase 2 trial
in neuroendocrine tumor patients suffering from carcinoid syndrome.