- Discovery of AZD9833, a Potent and Orally Bioavailable Selective Estrogen Receptor Degrader and Antagonist
-
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)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl]pyridin-3-amine (28). This compound was demonstrated to be a highly potent SERD that showed a pharmacological profile comparable to fulvestrant in its ability to degrade ERα in both MCF-7 and CAMA-1 cell lines. 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.
- Scott, James S.,Moss, Thomas A.,Balazs, Amber,Barlaam, Bernard,Breed, Jason,Carbajo, Rodrigo J.,Chiarparin, Elisabetta,Davey, Paul R. J.,Delpuech, Oona,Fawell, Stephen,Fisher, David I.,Gagrica, Sladjana,Gangl, Eric T.,Grebe, Tyler,Greenwood, Ryan D.,Hande, Sudhir,Hatoum-Mokdad, Holia,Herlihy, Kara,Hughes, Samantha,Hunt, Thomas A.,Huynh, Hoan,Janbon, Sophie L. M.,Johnson, Tony,Kavanagh, Stefan,Klinowska, Teresa,Lawson, Mandy,Lister, Andrew S.,Marden, Stacey,McGinnity, Dermot F.,Morrow, Christopher J.,Nissink, J. Willem M.,O'Donovan, Daniel H.,Peng, Bo,Polanski, Radoslaw,Stead, Darren S.,Stokes, Stephen,Thakur, Kumar,Throner, Scott R.,Tucker, Michael J.,Varnes, Jeffrey,Wang, Haixia,Wilson, David M.,Wu, Dedong,Wu, Ye,Yang, Bin,Yang, Wenzhan
-
supporting information
p. 14530 - 14559
(2021/01/05)
-
- CHEMICAL COMPOUNDS
-
The specification relates to compounds of Formula (I) and to pharmaceutically acceptable salts thereof, to processes and intermediates used for their preparation, to pharmaceutical compositions containing them and to their use in the treatment of cell pro
- -
-
Page/Page column 52; 53
(2019/01/17)
-
- Pd-tBuONO Cocatalyzed Aerobic Indole Synthesis
-
A Pd-tBuONO co-catalyzed scalable and practical synthesis of indoles with molecular oxygen as terminal oxidant is developed. Either terminal or internal 2-vinylanilines could be smoothly converted to desired indoles under one general condition. This method has been evaluated in the large scale synthesis of indomethacin and a potential anti-breast cancer drug candidate 1. (Figure presented.).
- Ning, Xiao-Shan,Liang, Xin,Hu, Kang-Fei,Yao, Chuan-Zhi,Qu, Jian-Ping,Kang, Yan-Biao
-
supporting information
p. 1590 - 1594
(2018/04/30)
-
- HETEROCYCLIC CGRP RECEPTOR ANTAGONISTS
-
The present invention is directed to heterocyclic compounds which are antagonists of CGRP receptors and may be useful in the treatment or prevention of diseases in which CGRP is involved, such as migraine. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved.
- -
-
Page/Page column 75
(2016/05/19)
-
- A new method for the synthesis of 2,6-dinitro and 2-halo-6-nitrostyrenes
-
A new method for the synthesis of 2-halo-6-nitrostyrenes from 2-halo-6-nitrotoluenes is disclosed. Also described is a one-pot process for the synthesis of 2,6-dinitristyrene from 2,6-dinitrotoluene. (C) 2000 Elsevier Science Ltd.
- Mundla
-
p. 6319 - 6321
(2007/10/03)
-
- Nucleoside derivatives with photolabile protective groups
-
The invention relates to nucleoside derivatives having photolabile protective groups of the general formula (I) STR1 in which R1 =H, NO2, CN, OCH3, halogen or alkyl or alkoxyalkyl having 1 to 4 C atoms R2 =H, OCH3 R3 =H, F, Cl, Br, NO2 R4 =H, halogen, OCH3, or an alkyl radical having 1 to 4 C atoms R5 =H or a usual functional group for preparing oligonucleotides R6 =H, OH, halogen or XR8, where X=O or S and R8 represents a protective group usual in nucleotide chemistry, B=adenine, cytosine, guanine, thymine, uracil, 2,6-diaminopurin-9-yl, hypoxanthin-9-yl, 5-methylcytosin-1-yl, 5-amino-4-imidazolcarboxamid-1-yl, or 5-amino-4-imidazolcarboxamid-3-yl, where in the case of B=adenine, cytosine or guanine, the primary amino function optionally exhibits a permanent protective group. These derivatives may be used for the light-controlled synthesis of oligonucleotides on a DNA chip.
- -
-
-
- New photolabile protecting groups in nucleoside and nucleotide chemistry - Synthesis, cleavage mechanisms and applications
-
New photolabile protecting groups have been found in the 2-(2- nitrophenyl)ethoxycarbonyl and the 2-(2-nitrophenyl)ethylsulfonyl group, respectively. The influence of substituents at the phenyl ring as well as the side-chain has been investigated regarding the photolysis rates on irradiation at 365 mn. β-Branching in the side-chain leads to highly increased rates of photodeprotection. A new type of photocleavage mechanism consisting of a photoinduced β-elimination process is proposed.
- Giegrich,Eisele-Buehler,Hermann,Kvasyuk,Charubala,Pfleiderer
-
p. 1987 - 1996
(2007/10/03)
-
- Ruthenium-Catalyzed Dehydrogenative N-Heterocyclization: Indoles from 2-Aminophenethyl Alcohols and 2-Nitrophenethyl Alcohols
-
Indole derivatives 3 were readily obtained from 2-aminophenethyl alcohols 1 in the presence of 2 mol percent (based on 1) of RuCl2(PPh3)3 under reflux in toluene.Indole (3a) was afforded from 2-aminophenethyl alcohol (1a) quantitatively.Other indoles (3) were also obtained in 73-99percent isolated yields from the corresponding 1, which were easily prepared by condensation between the corresponding 2-nitrotoluenes and aldehydes followed by reduction.During the reaction, a stoichiometric amount of hydrogen was spontaneously evolved into the gas phase.With a heterogeneous and homogeneous binary catalyst system, indoles were afforded in one pot from 2-nitrophenethyl alcohols 2 under a hydrogen atmosphere.
- Tsuji, Yasushi,Kotachi, Shinji,Huh, Keun-Tae,Watanabe, Yoshihisa
-
p. 580 - 584
(2007/10/02)
-