Journal of Medicinal Chemistry p. 1593 - 1608 (2019)
Update date:2022-08-17
Topics:
Scott, James S.
Bailey, Andrew
Buttar, David
Carbajo, Rodrigo J.
Curwen, Jon
Davey, Paul R. J.
Davies, Robert D. M.
Degorce, Sébastien L.
Donald, Craig
Gangl, Eric
Greenwood, Ryan
Groombridge, Sam D.
Johnson, Tony
Lamont, Scott
Lawson, Mandy
Lister, Andrew
Morrow, Christopher J.
Moss, Thomas A.
Pink, Jennifer H.
Polanski, Radoslaw
Herein, we report the identification and synthesis of a series of tricyclic indazoles as a novel class of selective estrogen receptor degrader antagonists. Replacement of a phenol, present in our previously reported tetrahydroisoquinoline scaffold, with an indazole group led to the removal of a reactive metabolite signal in an in vitro glutathione trapping assay. Further optimization, guided by X-ray crystal structures and NMR conformational work, varied the alkyl side chain and pendant aryl group and resulted in compounds with low turnover in human hepatocytes and enhanced chemical stability. Compound 9 was profiled as a representative of the series in terms of pharmacology and demonstrated the desired estrogen receptor α degrader-antagonist profile and demonstrated activity in a xenograft model of breast cancer.
View MoreZHEJIANG JIANYE CHEMICAL CO.,LTD.
Contact:86-571-64149273,64149234
Address:No. 48, Fuxi Road, Meicheng Town
Contact:86-571-85586718
Address:join hands science park,NO.4028 nanhuan road,hanghzou ,zhejiang,china
Contact:+86-134-5286-9121
Address:Add: Wing Tuck Commercial Centre, 177-183 Wing Lok Street, Hong Kong,
SHANGHAI RC CHEMICALS CO.,LTD.
website:http://www.rcc.net.cn
Contact:+86-21-50322175
Address:Rm1415 Yinqiao Masion No.58 Jinxin Road Pudong Shanghai China
Wuhan Sun-shine Bio-technology Corporation Limited
Contact:+862765522452
Address:武汉市东湖高新区高新二路388号生物医药加速器16栋501
Doi:10.1021/acs.joc.9b00872
(2019)Doi:10.1039/c0dt00773k
(2010)Doi:10.1002/ejoc.200300311
(2004)Doi:10.1016/j.jorganchem.2020.121276
(2020)Doi:10.1016/j.tetasy.2006.10.032
(2006)Doi:10.1081/NCN-200060305
(2005)