1 research outputs found
Discovery of MK-8318, a Potent and Selective CRTh2 Receptor Antagonist for the Treatment of Asthma
A novel series of
tricyclic tetrahydroquinolines were identified
as potent and selective CRTh2 receptor antagonists. The agonism and
antagonism switch was achieved through structure-based drug design
(SBDD) using a CRTh2 receptor homologue model. The challenge of very
low exposures in pharmacokinetic studies was overcome by exhaustive
medicinal chemistry lead optimization through focused SAR studies
on the tricyclic core. Further optimization resulted in the identification
of the preclinical candidate 4-(cyclopropyl((3<i>aS</i>,9<i>R</i>,9<i>aR</i>)-7-fluoro-4-(4-(trifluoromethoxy)benzoyl)-2,3,3<i>a</i>,4,9,9<i>a</i>-hexahydro-1<i>H</i>-cyclopenta[<i>b</i>]quinolin-9-yl)amino)-4-oxobutanoic acid (<b>15c</b>, <b>MK-8318</b>) with potent and selective CRTh2 antagonist
activity and a favorable PK profile suitable for once daily oral dosing
for potential treatment of asthma