1. Discovery of AMG 853, a CRTH2 and DP Dual Antagonist
- Author
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Zice Fu, Yongli Su, Xuemei Wang, Hua Lucy Tang, Timothy J. Sullivan, Lisa Seitz, Felix Gonzalez-Lopez de Turiso, Julio C. Medina, Mark P. Grillo, Shanna Lawlis, Ying Sun, Wang Shen, M.J. Schmitt, Qiuping Ye, Sarah E. Lively, Matthew L. Brown, An-Rong Li, Yingcai Wang, Bettina Van Lengerich, Jill Wait, Sujen Lai, Jiwen Liu, Michael G. Johnson, Jay Danao, Tassie L. Collins, and Qingge Xu
- Subjects
business.industry ,Organic Chemistry ,Antagonist ,Prostanoid ,Chemotaxis ,Pharmacology ,Phenylacetic acid ,medicine.disease ,Biochemistry ,chemistry.chemical_compound ,chemistry ,Drug Discovery ,Medicine ,Prostaglandin D2 ,business ,Receptor ,G protein-coupled receptor ,Asthma - 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.
- Published
- 2011