Discovery of an Acrylic Acid Based Tetrahydroisoquinoline as an Orally Bioavailable Selective Estrogen Receptor Degrader for ERα plus Breast Cancer

被引：40

作者：

Burks, Heather E. ^{[1
]}

Abrams, Tinya ^{[1
]}

Kirby, Christina A. ^{[1
]}

Baird, Jason ^{[1
]}

Fekete, Alexander ^{[1
]}

Hamann, Lawrence G. ^{[1
,3
]}

Kim, Sunkyu ^{[1
,4
]}

Lombardo, Franco ^{[1
,5
]}

Loo, Alice ^{[1
]}

Lubicka, Danuta ^{[1
]}

Macchi, Kaitlin ^{[1
]}

McDonnell, Donald P. ^{[2
]}

Mishina, Yuji ^{[1
]}

Norris, John D. ^{[2
]}

Nunez, Jill ^{[1
]}

Saran, Chitra ^{[1
]}

Sun, Yingchuan ^{[1
]}

Thomsen, Noel M. ^{[1
]}

Wang, Chunrong ^{[1
]}

Wang, Jianling ^{[1
,6
]}

Peukert, Stefan ^{[1
]}

机构：

[1] Novartis Inst BioMed Res, 181 Massachusetts Ave, Cambridge, MA 02139 USA

[2] Duke Univ, Sch Med, Dept Pharmacol & Canc Biol, Durham, NC 27710 USA

[3] Celgene, 200 Cambridge Pk Dr,Suite 3000, Cambridge, MA 02140 USA

[4] FORMA Therapeut, 500 Arsenal St,100, Watertown, MA 02472 USA

[5] Alkermes, 852 Winter St, Waltham, MA 02451 USA

[6] WuXi Apptec, 90 Delin Rd, Shanghai, Peoples R China

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2017年 / 60卷 / 07期

关键词：

POSTMENOPAUSAL WOMEN; ENDOCRINE RESISTANCE; PURE ANTIESTROGEN; STRUCTURAL BASIS; DOUBLE-BLIND; TAMOXIFEN; FULVESTRANT; THERAPY; TRIAL; ANTAGONISM;

D O I：

10.1021/acs.jmedchem.6b01468

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Tetrahydroisoquinoline 40 has been identified as a potent ER alpha antagonist and selective estrogen receptor degrader (SERD), exhibiting good oral bioavailability, antitumor efficacy, and SERD activity in vivo. We outline the discovery and chemical optimization of the THIQ scaffold leading to THIQ 40 and showcase the racemization of the scaffold, pharmacokinetic studies in preclinical species, and the in vivo efficacy of THIQ 40 in a MCF-7 human breast cancer xenograft model.

引用

页码：2790 / 2818

页数：29

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