Discovery of an orally-bioavailable CC Chemokine Receptor 2 antagonist derived from an acyclic diaminoalcohol backbone

Percy H Carter; Gregory D Brown; Sarah R King; Matthew E Voss; Andrew J Tebben; Robert J Cherney; Sandhya Mandlekar; Yvonne C Lo; Gengjie Yang; Persymphonie B Miller; Peggy A Scherle; Qihong Zhao; Carl P Decicco

doi:10.1016/j.bmcl.2012.03.007

Discovery of an orally-bioavailable CC Chemokine Receptor 2 antagonist derived from an acyclic diaminoalcohol backbone

Bioorg Med Chem Lett. 2012 May 1;22(9):3311-6. doi: 10.1016/j.bmcl.2012.03.007. Epub 2012 Mar 10.

Authors

Percy H Carter¹, Gregory D Brown, Sarah R King, Matthew E Voss, Andrew J Tebben, Robert J Cherney, Sandhya Mandlekar, Yvonne C Lo, Gengjie Yang, Persymphonie B Miller, Peggy A Scherle, Qihong Zhao, Carl P Decicco

Affiliation

¹ Research and Development, Bristol-Myers Squibb Company, Princeton, NJ 08543-4000, United States. [email protected]

PMID: 22475558
DOI: 10.1016/j.bmcl.2012.03.007

Abstract

We describe an isostere-driven approach to improve upon a previously-described series of capped dipeptide antagonists of CC Chemokine Receptor 2 (CCR2). Modification of the substitution around the isostere was combined with additional changes in a distal aromatic substituent to provide single-digit nanomolar antagonists of CCR2. These studies led to the identification of 18, a compound that was suitable for studies in murine models of CCR2 activity.

MeSH terms

Amino Alcohols / chemistry*
Amino Alcohols / pharmacology
Animals
Biological Availability
Mice
Receptors, CCR2 / antagonists & inhibitors*

Substances

Amino Alcohols
Receptors, CCR2