Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 9, Issue 7, Pages 679-684Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.8b00145
Keywords
MK-8318; CRTh2 receptor; DP2 receptor; receptor antagonist; homology model; PK lead optimization; pharmacokinetics; asthma; tetrahydroquinoline
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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((3aS,9R,9aR)-7-fluoro-4-(4-(trifluoromethoxy)benzoyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta [b] quinolin-9-yl) amino)-4-oxobutanoic acid (15c, MK-8318) with potent and selective CRTh2 antagonist activity and a favorable PK profile suitable for once daily oral dosing for potential treatment of asthma.
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