title: Novel, orally bioavailable gamma-aminoamide CC chemokine receptor 2 (CCR2) antagonists.
abstract: 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).
authors.affiliation: Department of Medicinal Chemistry and Department of Immunology/Rheumatology, Merck Research Laboratories, Rahway, New Jersey 07065, USA. alexander_pasternak@merck.com
authors.forename: Alexander
authors.initials: A
authors.lastname: Pasternak
authors.forename: Dominick
authors.initials: D
authors.lastname: Marino
authors.forename: Pasquale P
authors.initials: PP
authors.lastname: Vicario
authors.forename: Julia Marie
authors.initials: JM
authors.lastname: Ayala
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Cascierri
authors.forename: William
authors.initials: W
authors.lastname: Parsons
authors.forename: Sander G
authors.initials: SG
authors.lastname: Mills
authors.forename: Malcolm
authors.initials: M
authors.lastname: Maccoss
authors.forename: Lihu
authors.initials: L
authors.lastname: Yang
mesh_terms: 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
chemical_list: 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