Novel sulfone-containing di- and trisubstituted cyclohexanes as potent CC chemokine receptor 2 (CCR2) antagonists

• Published in: Bioorganic & medicinal chemistry letters Vol. 19; no. 13; pp. 3418 - 3422
• Main Authors: Cherney, Robert J., Mo, Ruowei, Meyer, Dayton T., Voss, Matthew E., Lo, Yvonne C., Yang, Gengjie, Miller, Persymphonie B., Scherle, Peggy A., Tebben, Andrew J., Carter, Percy H., Decicco, Carl P.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01-07-2009; Elsevier
• Subjects: Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; CCR2; CCR2 antagonist; Chemokine; Cyclohexanes - chemical synthesis; Cyclohexanes - chemistry; Cyclohexanes - pharmacology; GPCR; Medical sciences; Molecular Conformation; Pharmacology. Drug treatments; Receptors, CCR2 - antagonists & inhibitors; Receptors, CCR2 - metabolism; Sulfones - chemical synthesis; Sulfones - chemistry; Chemokine; GPCR; CCR2 antagonist; CCR2; Cyclohexane derivatives; Sulfone; CCR2 chemokine receptor; In vitro; Biological activity; Organic sulfide; G protein coupled receptor; Tertiary amine; Carboxamide; Benzamide derivatives; Antagonist; Fluorine Organic compounds; Chemical synthesis
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2009.05.041

Potent sulfone-containing di- and trisubstituted cyclohexanes were synthesized and evaluated as CC chemokine receptor 2 (CCR2) antagonists. This led to the trisubstituted derivative
54, which exhibited excellent binding (CCR2 IC
50
=
1.3
nM) and functional antagonism (calcium flux IC
50
=
0.5
nM and chemotaxis IC
50
=
0.2
nM). The superiority of the trisubstituted scaffold was rationalized to be the result of a conformational rigidification, which provided insight into the bioactive conformation of this chemotype.