Optimization of phenylacetic acid derivatives for CRTH2 and DP selective antagonism
We have previously reported that optimization of a series of phenylacetic acid derivatives led to the discovery of CRTH2 and DP dual antagonists, such as AMG 009 and AMG 853. During the optimization process, we discovered that minor structural modifications also afforded potent and selective CRTH2 or DP antagonists. Here we report the structure-activity relationship that led to the discovery of selective CRTH2 antagonists such as 2 and 17, and selective DP antagonists, such as 4 and 5.
Wang, Yingcai,Fu, Zice,Schmitt, Michael,Wang, Xuemei,Shen, Wang,Rickel, Erika,Martin, Tod,Budelsky, Alison,Marshall, Derek,Collins, Tassie,Tang, H. Lucy,Medina, Julio C.,Liu, Jiwen
scheme or table
p. 367 - 370
(2012/02/16)
Discovery of AMG 853, a CRTH2 and DP dual antagonist
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 rece
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.
scheme or table
p. 326 - 330
(2011/07/09)
Discovery and optimization of CRTH2 and DP dual antagonists
A series of phenylacetic acid derivatives was discovered as CRTH2 antagonists. Modification of the series led to compounds that are also antagonists of DP. Since activation of CRTH2 and DP are believed to play key roles in mediating responses of asthma and other immune diseases, this series was optimized to increase the dual antagonistic activities and improve pharmacokinetic properties. These efforts led to selection of AMG 009 as a clinical candidate.
Triphenylphosphine-mediated reductive cyclization of 2-nitrobiphenyls: A practical and convenient synthesis of carbazoles
The synthesis of a series of substituted carbazoles from the corresponding 2-nitrobiphenyl derivatives using a novel modification of the Cadogan reaction is described. Cyclization of the 2-nitrobiphenyls was achieved via reductive deoxygenation of the nitro groups using a slight excess of triphenylphosphine in a suitable solvent. We have observed a temperature dependence on the extent of conversion under these conditions, with higher boiling solvents affording higher yields across a range of substrates. The new reaction conditions are very straightforward and convenient to execute, tolerate a broad range of functional groups, and yield carbazole products in the absence of unwanted side products.
Freeman, Adam W.,Urvoy, Marie,Criswell, Megan E.
p. 5014 - 5019
(2007/10/03)
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