title: A novel series of N-(azetidin-3-yl)-2-(heteroarylamino)acetamide CCR2 antagonists.
abstract: The inflammatory response associated with the activation of C-C chemokine receptor CCR2 via it's interaction with the monocyte chemoattractant protein-1 (MCP-1, CCL2) has been implicated in many disease states, including rheumatoid arthritis, multiple sclerosis, atherosclerosis, asthma and neuropathic pain. Small molecule antagonists of CCR2 have been efficacious in animal models of inflammatory disease, and have been advanced into clinical development. The necessity to attenuate hERG binding appears to be a common theme for many of the CCR2 antagonist scaffolds appearing in the literature, presumably due the basic hydrophobic motif present in all of these molecules. Following the discovery of a novel cyclohexyl azetidinylamide CCR2 antagonist scaffold, replacement of the amide bond with heterocyclic rings was explored as a strategy for reducing hERG binding and improving pharmacokinetic properties.
authors.affiliation: Janssen Pharmaceutical Research & Development, L.L.C., Welsh & McKean Roads, Spring House, PA 19477, USA. NSUBASIN@its.jnj.com
authors.forename: Nalin L
authors.initials: NL
authors.lastname: Subasinghe
authors.forename: James
authors.initials: J
authors.lastname: Lanter
authors.forename: Thomas
authors.initials: T
authors.lastname: Markotan
authors.forename: Evan
authors.initials: E
authors.lastname: Opas
authors.forename: Sandra
authors.initials: S
authors.lastname: McKenney
authors.forename: Carl
authors.initials: C
authors.lastname: Crysler
authors.forename: Cuifen
authors.initials: C
authors.lastname: Hou
authors.forename: John
authors.initials: J
authors.lastname: O'Neill
authors.forename: Dana
authors.initials: D
authors.lastname: Johnson
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Sui
mesh_terms: D000081:Acetamides / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D001384:Azetidines / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors*
chemical_list: D000081:Acetamides; D001384:Azetidines; D054390:Receptors, CCR2