title: Discovery and pharmacological characterization of a novel rodent-active CCR2 antagonist, INCB3344.
abstract: This report describes the characterization of INCB3344, a novel, potent and selective small molecule antagonist of the mouse CCR2 receptor. The lack of rodent cross-reactivity inherent in the small molecule CCR2 antagonists discovered to date has precluded pharmacological studies of antagonists of this receptor and its therapeutic relevance. In vitro, INCB3344 inhibits the binding of CCL2 to mouse monocytes with nanomolar potency (IC(50) = 10 nM) and displays dose-dependent inhibition of CCL2-mediated functional responses such as ERK phosphorylation and chemotaxis with similar potency. Against a panel of G protein-coupled receptors that includes other CC chemokine receptors, INCB3344 is at least 100-fold selective for CCR2. INCB3344 possesses good oral bioavailability and systemic exposure in rodents that allows in vivo pharmacological studies. INCB3344 treatment results in a dose-dependent inhibition of macrophage influx in a mouse model of delayed-type hypersensitivity. The histopathological analysis of tissues from the delayed-type hypersensitivity model demonstrates that inhibition of CCR2 leads to a substantial reduction in tissue inflammation, suggesting that macrophages play an orchestrating role in immune-based inflammatory reactions. These results led to the investigation of INCB3344 in inflammatory disease models. We demonstrate that therapeutic dosing of INCB3344 significantly reduces disease in mice subjected to experimental autoimmune encephalomyelitis, a model of multiple sclerosis, as well as a rat model of inflammatory arthritis. In summary, we present the first report on the pharmacological characterization of a selective, potent and rodent-active small molecule CCR2 antagonist. These data support targeting this receptor for the treatment of chronic inflammatory diseases.
authors.affiliation: Incyte Corporation, Wilmington, DE 19880, USA.
authors.forename: Carrie M
authors.initials: CM
authors.lastname: Brodmerkel
authors.forename: Reid
authors.initials: R
authors.lastname: Huber
authors.forename: Maryanne
authors.initials: M
authors.lastname: Covington
authors.forename: Sharon
authors.initials: S
authors.lastname: Diamond
authors.forename: Leslie
authors.initials: L
authors.lastname: Hall
authors.forename: Robert
authors.initials: R
authors.lastname: Collins
authors.forename: Lynn
authors.initials: L
authors.lastname: Leffet
authors.forename: Karen
authors.initials: K
authors.lastname: Gallagher
authors.forename: Patricia
authors.initials: P
authors.lastname: Feldman
authors.forename: Paul
authors.initials: P
authors.lastname: Collier
authors.forename: Mark
authors.initials: M
authors.lastname: Stow
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Gu
authors.forename: Frederic
authors.initials: F
authors.lastname: Baribaud
authors.forename: Niu
authors.initials: N
authors.lastname: Shin
authors.forename: Beth
authors.initials: B
authors.lastname: Thomas
authors.forename: Tim
authors.initials: T
authors.lastname: Burn
authors.forename: Greg
authors.initials: G
authors.lastname: Hollis
authors.forename: Swamy
authors.initials: S
authors.lastname: Yeleswaram
authors.forename: Kim
authors.initials: K
authors.lastname: Solomon
authors.forename: Steve
authors.initials: S
authors.lastname: Friedman
authors.forename: Anlai
authors.initials: A
authors.lastname: Wang
authors.forename: Chu Biao
authors.initials: CB
authors.lastname: Xue
authors.forename: Robert C
authors.initials: RC
authors.lastname: Newton
authors.forename: Peggy
authors.initials: P
authors.lastname: Scherle
authors.forename: Kris
authors.initials: K
authors.lastname: Vaddi
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy; D002460:Cell Line; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000517:prevention & control; D005260:Female; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects / Q000276:immunology; D011759:Pyrrolidines / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics; D013329:Structure-Activity Relationship
chemical_list: C515335:Ccr2 protein, mouse; C515336:Ccr2 protein, rat; C505875:INCB3344; D011759:Pyrrolidines; D054390:Receptors, CCR2; D019707:Receptors, Chemokine