title: Discovery, optimization, and pharmacological characterization of novel heteroaroylphenylureas antagonists of C-C chemokine ligand 2 function.
abstract: Through the application of TRAP (target-related affinity profiling), we identified a novel class of heteroaroylphenylureas that inhibit human CCL2-induced chemotaxis of monocytes/macrophages both in vitro and in vivo. This inhibition was concentration-dependent and selective with regard to other chemokines. The compounds, however, did not antagonize the binding of (125)I-labeled CCL2 to the CCR2 receptor nor did they block CCR2-mediated signal transduction responses such as calcium mobilization. Optimization of early leads for potency and pharmacokinetic parameters resulted in the identification of 17, a potent inhibitor of chemotaxis (IC(50) = 80 nM) with excellent oral bioavailability in rats (F = 60%). Compound 17 reduced swelling and joint destruction in two rat models of rheumatoid arthritis and delayed disease onset and produced near complete resolution of symptoms in a mouse model of multiple sclerosis.
authors.affiliation: Telik, Inc., 700 Hansen Way, Palo Alto, California 94304, United States. elaborde@telik.com
authors.forename: Edgardo
authors.initials: E
authors.lastname: Laborde
authors.forename: Robert W
authors.initials: RW
authors.lastname: Macsata
authors.forename: Fanying
authors.initials: F
authors.lastname: Meng
authors.forename: Brian T
authors.initials: BT
authors.lastname: Peterson
authors.forename: Louise
authors.initials: L
authors.lastname: Robinson
authors.forename: Steve R
authors.initials: SR
authors.lastname: Schow
authors.forename: Reyna J
authors.initials: RJ
authors.lastname: Simon
authors.forename: Hua
authors.initials: H
authors.lastname: Xu
authors.forename: Kunihisa
authors.initials: K
authors.lastname: Baba
authors.forename: Hideaki
authors.initials: H
authors.lastname: Inagaki
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Ishiwata
authors.forename: Takahito
authors.initials: T
authors.lastname: Jomori
authors.forename: Yukiharu
authors.initials: Y
authors.lastname: Matsumoto
authors.forename: Atsushi
authors.initials: A
authors.lastname: Miyachi
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakamura
authors.forename: Masayuki
authors.initials: M
authors.lastname: Okamoto
authors.forename: Tracy M
authors.initials: TM
authors.lastname: Handel
authors.forename: Claude C A
authors.initials: CC
authors.lastname: Bernard
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000473:pathology; D001682:Biological Availability; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D016466:CHO Cells; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors*; D002633:Chemotaxis / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D007596:Joints / Q000187:drug effects / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008813:Mice, Inbred ICR; D009000:Monocytes / Q000187:drug effects / Q000502:physiology; D009103:Multiple Sclerosis / Q000188:drug therapy; D010671:Phenylurea Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D054390:Receptors, CCR2 / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C558737:1-(6-((2-(dimethylamino)ethyl)(methyl)amino)-1,3-dimethyl-1H-pyrazolo(3,4-b)pyridine-5-carbonyl)-3-(3-isopropoxyphenyl)urea; D000894:Anti-Inflammatory Agents, Non-Steroidal; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018932:Chemokine CCL2; D010671:Phenylurea Compounds; D054390:Receptors, CCR2