title: 4-Amino-2-alkyl-butyramides as small molecule CCR2 antagonists with favorable pharmacokinetic properties.
abstract: 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 = 4 nM, 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.
authors.affiliation: Merck Research Laboratories, Rahway, NJ 07065, USA. gabor_butora@merck.com
authors.forename: Gabor
authors.initials: G
authors.lastname: Butora
authors.forename: Gregori J
authors.initials: GJ
authors.lastname: Morriello
authors.forename: Shankaran
authors.initials: S
authors.lastname: Kothandaraman
authors.forename: Deodialsingh
authors.initials: D
authors.lastname: Guiadeen
authors.forename: Alexander
authors.initials: A
authors.lastname: Pasternak
authors.forename: William H
authors.initials: WH
authors.lastname: Parsons
authors.forename: Malcolm
authors.initials: M
authors.lastname: MacCoss
authors.forename: Pasquale P
authors.initials: PP
authors.lastname: Vicario
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Cascieri
authors.forename: Lihu
authors.initials: L
authors.lastname: Yang
mesh_terms: D000478:Alkylation; D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics*; D000586:Amination; D000818:Animals; D002478:Cells, Cultured; D006224:Cricetinae; D006801:Humans; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; C515334:CCR2 protein, human; C515336:Ccr2 protein, rat; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; C006866:butyramide