title: Potent antagonists of the CCR2b receptor. Part 3: SAR of the (R)-3-aminopyrrolidine series.
abstract: SAR studies were conducted around lead compound 1 using high-throughput parallel solution and solid phase synthesis. Our lead optimization efforts led to the identification of several CCR2b antagonists with potent activity in both binding and functional assays [Compound 71 CCR2b Binding IC(50) 3.2 nM; MCP-1-Induced Chemotaxis IC(50) 0.83 nM; Ca(2+) Flux IC(50) 7.5 nM].
authors.affiliation: Deltagen Research Laboratories (Former CombiChem, Inc.), 4570 Executive Drive, San Diego, CA 92121, USA. wmoree@neurocrine.com
authors.forename: Wilna J
authors.initials: WJ
authors.lastname: Moree
authors.forename: Ken-ichiro
authors.initials: K
authors.lastname: Kataoka
authors.forename: Michele M
authors.initials: MM
authors.lastname: Ramirez-Weinhouse
authors.forename: Tatsuki
authors.initials: T
authors.lastname: Shiota
authors.forename: Minoru
authors.initials: M
authors.lastname: Imai
authors.forename: Takaharu
authors.initials: T
authors.lastname: Tsutsumi
authors.forename: Masaki
authors.initials: M
authors.lastname: Sudo
authors.forename: Noriaki
authors.initials: N
authors.lastname: Endo
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Muroga
authors.forename: Takahiko
authors.initials: T
authors.lastname: Hada
authors.forename: Dewey
authors.initials: D
authors.lastname: Fanning
authors.forename: John
authors.initials: J
authors.lastname: Saunders
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Kato
authors.forename: Peter L
authors.initials: PL
authors.lastname: Myers
authors.forename: Christine M
authors.initials: CM
authors.lastname: Tarby
mesh_terms: D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism*; D002633:Chemotaxis / Q000187:drug effects*; D002851:Chromatography, High Pressure Liquid; D005453:Fluorescence; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000494:pharmacology*; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014162:Transfection
chemical_list: C111835:CCL2 protein, human; C515334:CCR2 protein, human; D018932:Chemokine CCL2; D011759:Pyrrolidines; D054390:Receptors, CCR2; D002118:Calcium