Herein we report the optimization of a series of tricyclic indazoles as selective estrogen receptor degraders (serd) and antagonists for the treatment of er breast cancer. structure based design together with systematic investigation of each region of the molecular architecture led to the identification of n [1 (3 fluoropropyl)azetidin 3 yl] 6 [(6s,8r) 8 methyl 7 (2,2,2 trifluoroethyl) 6,7,8. A stringent control of lipophilicity ensured that 28 had favorable physicochemical and preclinical pharmacokinetic properties for oral administration. this, combined with demonstration of potent in vivo activity in mouse xenograft models, resulted in progression of this compound, also known as azd9833, into clinical trials.
Hopes in exploring potent oral serds were at risk until the advent of the three oral serds: sar439859 32 (13), azd9833 33 (14), and gdc 9545 34 (15), which are under phase iii trials now. these. This compound was demonstrated to be a highly potent serd which showed a comparable pharmacological profile to fulvestrant in its ability to degrade er in both mcf 7 and cama 1 cell lines. herein we report the optimization of a series of tricyclic indazoles as selective estrogen receptor degraders (serd) and antagonists for the treatment of er breast cancer. structure based design together. View this abstract online; discovery of azd9833, a potent and orally bioavailable selective estrogen receptor degrader and antagonist. j med chem. 2020; 63(23):14530 14559 (issn: 1520 4804). Building on that learning, extensive structure enabled chemical optimization has resulted in the identification of a next generation oral serd azd9833, a potent degrader and antagonist of the erα receptor (both ec 50 <1 nm in mcf7 cells) with favorable physicochemical properties (logd 7.4 <3).
View this abstract online; discovery of azd9833, a potent and orally bioavailable selective estrogen receptor degrader and antagonist. j med chem. 2020; 63(23):14530 14559 (issn: 1520 4804). Building on that learning, extensive structure enabled chemical optimization has resulted in the identification of a next generation oral serd azd9833, a potent degrader and antagonist of the erα receptor (both ec 50 <1 nm in mcf7 cells) with favorable physicochemical properties (logd 7.4 <3). Herein, we report the optimization of a meta substituted series of selective estrogen receptor degrader (serd) antagonists for the treatment of er breast cancer. structure based design together with the use of modeling and nmr to favor the bioactive conformation led to a highly potent series of basic serds with promising physicochemical properties. issues with herg activity resulted in a. Discovery of a potent and orally bioavailable zwitterionic series of selective estrogen receptor degrader antagonists. scott js 1 , stead d 1 ,.
Herein, we report the optimization of a meta substituted series of selective estrogen receptor degrader (serd) antagonists for the treatment of er breast cancer. structure based design together with the use of modeling and nmr to favor the bioactive conformation led to a highly potent series of basic serds with promising physicochemical properties. issues with herg activity resulted in a. Discovery of a potent and orally bioavailable zwitterionic series of selective estrogen receptor degrader antagonists. scott js 1 , stead d 1 ,.
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