Design, synthesis, and structure–activity relationship of novel CCR2 antagonists

• Published in: Bioorganic & medicinal chemistry letters Vol. 19; no. 6; pp. 1830 - 1834
• Main Authors: Kothandaraman, Shankaran, Donnely, Karla L., Butora, Gabor, Jiao, Richard, Pasternak, Alexander, Morriello, Gregori J., Goble, Stephen D., Zhou, Changyou, Mills, Sander G., MacCoss, Malcolm, Vicario, Pasquale P., Ayala, Julia M., DeMartino, Julie A., Struthers, Mary, Cascieri, Margaret A., Yang, Lihu
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15.03.2009; Elsevier
• Subjects: Administration, Oral; Aminocyclopentane carboxamide; Animals; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; CCR2 Antagonist; Chemistry, Pharmaceutical - methods; Chemotaxis; Dogs; Drug Design; Humans; Inhibitory Concentration 50; Macaca mulatta; Medical sciences; Models, Chemical; Molecular Structure; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; Receptors, CCR2 - antagonists & inhibitors; Receptors, CCR2 - chemistry; Reductive aminations; Structure-Activity Relationship; CCR2 Antagonist; Reductive aminations; Chemotaxis; Aminocyclopentane carboxamide; Rat; Monkey; Chemical reduction; Amination; Structure activity relation; Primates; Antagonist; Chemical synthesis; Dog; Fissipedia; Carnivora; Aminoamide; Rodentia; Pyran derivatives; Oral administration; CCR2 chemokine receptor; Vertebrata; Mammalia; Animal; Carboxamide; Fluorine Organic compounds; Pharmacokinetics; Cyclopentane derivatives
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2008.12.050

Discovery of a novel series of 3-aminocyclopentanecarboxamide CCR2 receptor antagonists are presented herein. These compounds demonstrate high affinity and functional inhibition of hCCR2 receptors. A discussion on SAR along with the cross species PK profile for the best analog ( 59) is also included. A series of novel 1-aminocyclopentyl-3-carboxyamides incorporating substituted tetrahydropyran moieties have been synthesized and subsequently evaluated for their antagonistic activity against the human CCR2 receptor. Among them analog 59 was found to posses potent antagonistic activity.