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Discovery of AMG 853, a CRTH2 and DP Dual Antagonist.

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.

SUBMITTER: Liu J

PROVIDER: S-EPMC4018074 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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Discovery of AMG 853, a CRTH2 and DP Dual Antagonist.

Liu Jiwen J Li An-Rong AR Wang Yingcai Y Johnson Mike G MG Su Yongli Y Shen Wang W Wang Xuemei X Lively Sarah S Brown Matthew M Lai SuJen S Gonzalez Lopez De Turiso Felix F Xu Qingge Q Van Lengerich Bettina B Schmitt Mike M Fu Zice Z Sun Ying Y Lawlis Shanna S Seitz Lisa L Danao Jay J Wait Jill J Ye Qiuping Q Tang Hua Lucy HL Grillo Mark M Collins Tassie L TL Sullivan Timothy J TJ Medina Julio C JC

ACS medicinal chemistry letters 20110302 5

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 ...[more]

PMID: 24900313

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