4-Amino-2-alkyl-butyramides as small molecule CCR2 antagonists with favorable pharmacokinetic properties.
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.
Butora
Gabor
G
Merck Research Laboratories, Rahway, NJ 07065, USA. gabor_butora@merck.com
Morriello
Gregori J
GJ
Kothandaraman
Shankaran
S
Guiadeen
Deodialsingh
D
Pasternak
Alexander
A
Parsons
William H
WH
MacCoss
Malcolm
M
Vicario
Pasquale P
PP
Cascieri
Margaret A
MA
Yang
Lihu
L
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
D000577:Amides; C515334:CCR2 protein, human; C515336:Ccr2 protein, rat; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; C006866:butyramide