2. Academic Validation
  3. Discovery of MK-8318, a Potent and Selective CRTh2 Receptor Antagonist for the Treatment of Asthma

Discovery of MK-8318, a Potent and Selective CRTh2 Receptor Antagonist for the Treatment of Asthma

  • ACS Med Chem Lett. 2018 Jun 23;9(7):679-684. doi: 10.1021/acsmedchemlett.8b00145.
Xianhai Huang 1,  Jason Brubaker 2,  Wei Zhou 1,  Purakkattle J Biju 1,  Li Xiao 1,  Ning Shao 1,  Ying Huang 1,  Li Dong 1,  Zhidan Liu 1,  Rema Bitar 1,  Alexei Buevich 1,  Joon Jung 2,  Scott L Peterson 2,  John W Butcher 2,  Joshua Close 2,  Michelle Martinez 2,  Rachel N MacCoss 2,  Hongjun Zhang 2,  Scott Crawford 2,  Kevin D McCormick 1,  Robert Aslanian 1,  Ravi Nargund 1,  Craig Correll 2,  Francois Gervais 2,  Hongchen Qiu 1,  Xiaoxin Yang 1,  Charles Garlisi 1,  Diane Rindgen 1,  Kevin M Maloney 1,  Phieng Siliphaivanh 2,  Anandan Palani 1
Affiliations

Affiliations

  • 1 Discovery Chemistry, In Vitro Pharmacology, Drug Metabolism and Pharmacokinetics, and Process Chemistry, Merck Research Laboratory, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
  • 2 Discovery Chemistry and Immunology, Merck Research Laboratory, 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
PMID: 30034600 DOI: 10.1021/acsmedchemlett.8b00145
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.

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