4-Amino-2-alkyl-butyramides as small molecule CCR2 antagonists with favorable pharmacokinetic properties

• Published in: Bioorganic & medicinal chemistry letters 2006-09, Vol.16 (18), p.4715-4722
• Main Authors: Butora, Gabor, Morriello, Gregori J., Kothandaraman, Shankaran, Guiadeen, Deodialsingh, Pasternak, Alexander, Parsons, William H., MacCoss, Malcolm, Vicario, Pasquale P., Cascieri, Margaret A., Yang, Lihu
• Format: Article
• Language: English
• Subjects: Alkylation; Amides - chemical synthesis; Amides - chemistry; Amides - pharmacokinetics; Amination; Animals; Antagonists; Biological and medical sciences; CCR2; Cells, Cultured; Chemokines; Cricetinae; Humans; Medical sciences; Miscellaneous; Molecular Structure; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; Receptors, CCR2; Receptors, Chemokine - antagonists & inhibitors; Receptors, Chemokine - metabolism; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2006.07.011

A novel class of CCR2 antagonists with high binding affinity (IC50=4nM, human monocyte) and favorable pharmacokinetic profile is described. A systematic examination of the central aromatic portion of the lead (2S)-N-[3,5-bis(trifluoromethyl)benzyl]-2-(4-fluorophenyl)-4-(1′H-spiro[indene-1,4′-piperidin]-1′-yl)butanamide (9) led to the discovery of a novel class of CCR2 receptor antagonists, which carry small alicyclic groups such as cyclopropyl, cylobutyl, or cyclopropylmethyl attached at C2 of the carbon backbone. The most potent compound discovered, namely (2S)-N-[3,5-bis(trifluoromethyl)benzyl]-2-cyclopropyl-4-[(1R,3′R)-3′-methyl-1′H-spiro[indene-1,4′-piperidin]-1′-yl]butanamide (29), showed very high binding affinity (IC50=4nM, human monocyte) and excellent selectivity toward other related chemokine receptors. The excellent pharmacokinetic profile of this new lead compound allows for extensive in vivo evaluation.