| Literature DB >> 30034600 |
Xianhai Huang1, Jason Brubaker2, Wei Zhou1, Purakkattle J Biju1, Li Xiao1, Ning Shao1, Ying Huang1, Li Dong1, Zhidan Liu1, Rema Bitar1, Alexei Buevich1, Joon Jung2, Scott L Peterson2, John W Butcher2, Joshua Close2, Michelle Martinez2, Rachel N MacCoss2, Hongjun Zhang2, Scott Crawford2, Kevin D McCormick1, Robert Aslanian1, Ravi Nargund1, Craig Correll2, Francois Gervais2, Hongchen Qiu1, Xiaoxin Yang1, Charles Garlisi1, Diane Rindgen1, Kevin M Maloney1, Phieng Siliphaivanh2, Anandan Palani1.
Abstract
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.Entities:
Year: 2018 PMID： 30034600 PMCID： PMC6047040 DOI： 10.1021/acsmedchemlett.8b00145
Source DB: PubMed Journal: ACS Med Chem Lett ISSN： 1948-5875 Impact factor: 4.345