Potent antagonists of the CCR2b receptor. Part 3: SAR of the (R)-3-aminopyrrolidine series.
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].
Moree
Wilna J
WJ
Deltagen Research Laboratories (Former CombiChem, Inc.), 4570 Executive Drive, San Diego, CA 92121, USA. wmoree@neurocrine.com
Kataoka
Ken-ichiro
K
Ramirez-Weinhouse
Michele M
MM
Shiota
Tatsuki
T
Imai
Minoru
M
Tsutsumi
Takaharu
T
Sudo
Masaki
M
Endo
Noriaki
N
Muroga
Yumiko
Y
Hada
Takahiko
T
Fanning
Dewey
D
Saunders
John
J
Kato
Yoshinori
Y
Myers
Peter L
PL
Tarby
Christine M
CM
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
C111835:CCL2 protein, human; C515334:CCR2 protein, human; D018932:Chemokine CCL2; D011759:Pyrrolidines; D054390:Receptors, CCR2; D002118:Calcium