Discovery of AMG 853, a CRTH2 and DP Dual Antagonist

  • ACS Med Chem Lett. 2011 Mar 2;2(5):326-30. doi: 10.1021/ml1002234.
Jiwen Liu  1 ,  An-Rong Li  1 ,  Yingcai Wang  1 ,  Mike G Johnson  1 ,  Yongli Su  1 ,  Wang Shen  1 ,  Xuemei Wang  1 ,  Sarah Lively  1 ,  Matthew Brown  1 ,  SuJen Lai  1 ,  Felix Gonzalez Lopez De Turiso  1 ,  Qingge Xu  1 ,  Bettina Van Lengerich  1 ,  Mike Schmitt  1 ,  Zice Fu  1 ,  Ying Sun  1 ,  Shanna Lawlis  1 ,  Lisa Seitz  1 ,  Jay Danao  1 ,  Jill Wait  1 ,  Qiuping Ye  1 ,  Hua Lucy Tang  1 ,  Mark Grillo  1 ,  Tassie L Collins  1 ,  Timothy J Sullivan  1 ,  Julio C Medina  1
Affiliations
  • 1. Amgen Inc., 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
PMID: 24900313 DOI: 10.1021/ml1002234
Abstract

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.

Keywords
AMG 853; CRTH2 receptor; DP receptor; antagonist; asthma; prostaglandin D2.
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