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Discovery of AZD9833, a potent and orally bioavailable selective estrogen receptor degrader and antagonist.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-09-10 , DOI: 10.1021/acs.jmedchem.0c01163 James S Scott 1 , Thomas A Moss 1 , Amber Balazs 2 , Bernard Barlaam 1 , Jason Breed 3 , Rodrigo J Carbajo 1 , Elisabetta Chiarparin 1 , Paul R J Davey 1 , Oona Delpuech 1 , Stephen Fawell 2 , David I Fisher 3 , Sladjana Gagrica 1 , Eric T Gangl 2 , Tyler Grebe 2 , Ryan D Greenwood 1 , Sudhir Hande 2 , Holia Hatoum-Mokdad 2 , Kara Herlihy 3 , Samantha Hughes 1 , Thomas A Hunt 1 , Hoan Huynh 2 , Sophie L M Janbon 4 , Tony Johnson 1 , Stefan Kavanagh 5 , Teresa Klinowska 1 , Mandy Lawson 1 , Andrew S Lister 1 , Stacey Marden 6 , Dermot F McGinnity 1 , Christopher J Morrow 1 , J Willem M Nissink 1 , Daniel H O'Donovan 1 , Bo Peng 2 , Radoslaw Polanski 3 , Darren S Stead 1 , Stephen Stokes 1 , Kumar Thakur 2 , Scott R Throner 2 , Michael J Tucker 1 , Jeffrey Varnes 2 , Haixia Wang 2 , David M Wilson 1 , Dedong Wu 6 , Ye Wu 2 , Bin Yang 2 , Wenzhan Yang 6
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-09-10 , DOI: 10.1021/acs.jmedchem.0c01163 James S Scott 1 , Thomas A Moss 1 , Amber Balazs 2 , Bernard Barlaam 1 , Jason Breed 3 , Rodrigo J Carbajo 1 , Elisabetta Chiarparin 1 , Paul R J Davey 1 , Oona Delpuech 1 , Stephen Fawell 2 , David I Fisher 3 , Sladjana Gagrica 1 , Eric T Gangl 2 , Tyler Grebe 2 , Ryan D Greenwood 1 , Sudhir Hande 2 , Holia Hatoum-Mokdad 2 , Kara Herlihy 3 , Samantha Hughes 1 , Thomas A Hunt 1 , Hoan Huynh 2 , Sophie L M Janbon 4 , Tony Johnson 1 , Stefan Kavanagh 5 , Teresa Klinowska 1 , Mandy Lawson 1 , Andrew S Lister 1 , Stacey Marden 6 , Dermot F McGinnity 1 , Christopher J Morrow 1 , J Willem M Nissink 1 , Daniel H O'Donovan 1 , Bo Peng 2 , Radoslaw Polanski 3 , Darren S Stead 1 , Stephen Stokes 1 , Kumar Thakur 2 , Scott R Throner 2 , Michael J Tucker 1 , Jeffrey Varnes 2 , Haixia Wang 2 , David M Wilson 1 , Dedong Wu 6 , Ye Wu 2 , Bin Yang 2 , Wenzhan Yang 6
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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.
中文翻译：
发现AZD9833，一种有效且可口服生物利用的选择性雌激素受体降解剂和拮抗剂。
本文中，我们报道了一系列三环吲唑作为选择性雌激素受体降解剂（SERD）和拮抗剂的优化，用于治疗ER +乳腺癌。基于结构的设计以及对分子结构每个区域的系统研究，导致了N- [1-（3-氟丙基）氮杂环丁烷-3-基] -6-[（6 S，8 R）-8-甲基的鉴定-7-（2,2,2-三氟乙基）-6,7,8,9-四氢-3 H-吡唑并[4,3- f ]异喹啉-6-基]吡啶-3-胺（28）。该化合物被证明是高效的SERD，在MCF-7和CAMA-1细胞系中均具有与氟维司群相当的药理学特征，能够降解ERα。严格控制亲脂性可确保28口服具有良好的理化和临床前药代动力学特性。这与小鼠异种移植模型中体内有效活性的证明相结合，导致该化合物（也称为AZD9833）进入临床试验。
更新日期：2020-09-10
中文翻译：
发现AZD9833，一种有效且可口服生物利用的选择性雌激素受体降解剂和拮抗剂。
本文中，我们报道了一系列三环吲唑作为选择性雌激素受体降解剂（SERD）和拮抗剂的优化，用于治疗ER +乳腺癌。基于结构的设计以及对分子结构每个区域的系统研究，导致了N- [1-（3-氟丙基）氮杂环丁烷-3-基] -6-[（6 S，8 R）-8-甲基的鉴定-7-（2,2,2-三氟乙基）-6,7,8,9-四氢-3 H-吡唑并[4,3- f ]异喹啉-6-基]吡啶-3-胺（28）。该化合物被证明是高效的SERD，在MCF-7和CAMA-1细胞系中均具有与氟维司群相当的药理学特征，能够降解ERα。严格控制亲脂性可确保28口服具有良好的理化和临床前药代动力学特性。这与小鼠异种移植模型中体内有效活性的证明相结合，导致该化合物（也称为AZD9833）进入临床试验。
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