CRTH2和DP双重拮抗剂AMG 853的发现。
Discovery of AMG 853, a CRTH2 and DP Dual Antagonist.
作者信息
Liu Jiwen, Li An-Rong, Wang Yingcai, Johnson Mike G, Su Yongli, Shen Wang, Wang Xuemei, Lively Sarah, Brown Matthew, Lai SuJen, Gonzalez Lopez De Turiso Felix, Xu Qingge, Van Lengerich Bettina, Schmitt Mike, Fu Zice, Sun Ying, Lawlis Shanna, Seitz Lisa, Danao Jay, Wait Jill, Ye Qiuping, Tang Hua Lucy, Grillo Mark, Collins Tassie L, Sullivan Timothy J, Medina Julio C
机构信息
Amgen Inc., 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
出版信息
ACS Med Chem Lett. 2011 Mar 2;2(5):326-30. doi: 10.1021/ml1002234. eCollection 2011 May 12.
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.
摘要
前列腺素D2（PGD2）在介导哮喘、过敏性鼻炎和特应性皮炎中出现的过敏反应方面发挥着关键作用。PGD2通过两种G蛋白偶联受体（GPCR）发挥其活性，即前列腺素D受体（DP或DP1）和在Th2细胞上表达的趋化因子受体同源分子（CRTH2或DP2）。我们报告了一系列苯乙酸衍生物的优化情况，旨在提高AMG 009对DP和CRTH2的双重活性。这些努力促成了AMG 853（2-(4-(4-(叔丁基氨基甲酰基)-2-(2-氯-4-环丙基苯基磺酰胺基)苯氧基)-5-氯-2-氟苯基)乙酸）的发现，该化合物正在进行哮喘的人体临床试验评估。
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