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Discovery of AMG 853, a CRTH2 and DP Dual Antagonist

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journal contribution
posted on 12.05.2011, 00:00 by Jiwen Liu, An-Rong Li, Yingcai Wang, Mike G. Johnson, Yongli Su, Wang Shen, Xuemei Wang, Sarah Lively, Matthew Brown, SuJen Lai, Felix Gonzalez Lopez De Turiso, Qingge Xu, Bettina Van Lengerich, Mike Schmitt, Zice Fu, Ying Sun, Shanna Lawlis, Lisa Seitz, Jay Danao, Jill Wait, Qiuping Ye, Hua Lucy Tang, Mark Grillo, Tassie L. Collins, Timothy J. Sullivan, Julio C. Medina
Prostaglandin D2 (PGD2) plays a key role in mediating allergic reactions seen in asthma, allergic rhinitis, and atopic dermatitis. PGD2 exerts its activity through two G protein-coupled receptors (GPCRs), prostanoid D receptor (DP or DP1), and chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2 or DP2). We report the optimization of a series of phenylacetic acid derivatives in an effort to improve the dual activity of AMG 009 against DP and CRTH2. These efforts led to the discovery of AMG 853 (2-(4-(4-(tert-butylcarbamoyl)-2-(2-chloro-4-cyclopropylphenyl sulfonamido)phenoxy)-5-chloro-2-fluorophenyl)acetic acid), which is being evaluated in human clinical trials for asthma.