The discovery of MK-0812, a potent and selective CCR2 antagonist


Lihu Yang, lihu_yang@merck.com1, Richard X. Jiao1, Chris Moyes2, Greg Morriello2, Gabor Butora, gabor_butora@merck.com2, K. Shankaran2, Alexander Pasternak, alexander_pasternak@merck.com1, Steve Goble, stephen_goble@merck.com1, Changyou Zhou, changyou_zhou@merck.com1, Malcolm MacCoss1, Anne-Marie Cumiskey2, Larry Peterson2, Mike Forrest2, Julia M. Ayala3, Hong Jin2, Julie DeMartino2, and Sander G. Mills1. (1) Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065-0900, (2) Merck Research Laboratories, Rahway, NJ 07065, (3) Department of Immunology, Merck Research Laboratories, Rahway, NJ 07065-0900
Monocyte chemoattractant protein (MCP-1/CCL2) is a CC chemokine and binds to chemokine receptor 2 (CCR2), which is expressed on the majority of blood born monocytes. CCR2 antagonism has been suggested as a viable approach for the treatment of a variety of inflammatory and autoimmune diseases including rheumatoid arthritis, multiple sclerosis and atherosclerosis. The SAR evolution that led to the clinical candidate MK-0812 will be discussed. MK-0812 is a potent and selective CCR2 antagonist with low nM affinity for CCR2 on human monocytes and low nM in the chemotaxis assay. It has good PK profiles in preclinical species and demonstrated efficacy in animal models.

First Time Disclosure of Clinical Candidates
1:30 PM-5:30 PM, Sunday, March 25, 2007 McCormick Place Lakeside -- Room E353 A/B, Level 3, Oral

Division of Medicinal Chemistry

The 233rd ACS National Meeting, Chicago, IL, March 25-29, 2007