Novel, orally bioavailable gamma-aminoamide CC chemokine receptor 2 (CCR2) antagonists.
Through modification of a screening hit we have discovered a structurally distinct new lead, (2S)-N-[3,5-bis(trifluoromethyl)benzyl]-2-(4-fluorophenyl)-4-(4-phenylpiperidin-1-yl)butanamide (11), which has subsequently served as the departure point for an ongoing program targeting CCR2 antagonists. Optimization of 11 leading to antagonists 26 and 37 is described. Antagonist 26 was shown to have good oral bioavailability in rats. Antagonist 37 had a CCR2 IC50 of 59 nM and excellent potency in a functional assay measuring inhibition of MCP-1 induced monocyte chemotaxis (IC50 of 41 nM).
Pasternak
Alexander
A
Department of Medicinal Chemistry and Department of Immunology/Rheumatology, Merck Research Laboratories, Rahway, New Jersey 07065, USA. alexander_pasternak@merck.com
Marino
Dominick
D
Vicario
Pasquale P
PP
Ayala
Julia Marie
JM
Cascierri
Margaret A
MA
Parsons
William
W
Mills
Sander G
SG
Maccoss
Malcolm
M
Yang
Lihu
L
D000284:Administration, Oral; D000577:Amides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001682:Biological Availability; D065100:CCR5 Receptor Antagonists; D018932:Chemokine CCL2 / Q000494:pharmacology; D002634:Chemotaxis, Leukocyte; D066298:In Vitro Techniques; D007192:Indenes / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects / Q000502:physiology; D010880:Piperidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D054390:Receptors, CCR2; D019713:Receptors, CCR5 / Q000378:metabolism; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000577:Amides; D065100:CCR5 Receptor Antagonists; C515336:Ccr2 protein, rat; D018932:Chemokine CCL2; D007192:Indenes; C513359:N-(3,5-bis(trifluoromethyl)benzyl)-2-(4-fluorophenyl)-4-(4-phenylpiperidin-1-yl)butanamide; D010880:Piperidines; D054390:Receptors, CCR2; D019713:Receptors, CCR5; D019707:Receptors, Chemokine; D018040:Receptors, Neurokinin-1; D013141:Spiro Compounds