Discovery of AMG 853, a CRTH2 and DP Dual Antagonist.
Liu J, Li AR, Wang Y, Johnson MG, Su Y, Shen W, Wang X, Lively S, Brown M, Lai S, Gonzalez Lopez De Turiso F, Xu Q, Van Lengerich B, Schmitt M, Fu Z, Sun Y, Lawlis S, Seitz L, Danao J, Wait J, Ye Q, Tang HL, Grillo M, Collins TL, Sullivan TJ, Medina JC.
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.