Discovery of an Acrylic Acid Based Tetrahydroisoquinoline as an Orally Bioavailable Selective Estrogen Receptor Degrader for ERα+ Breast Cancer
作者:Heather E. Burks、Tinya Abrams、Christina A. Kirby、Jason Baird、Alexander Fekete、Lawrence G. Hamann、Sunkyu Kim、Franco Lombardo、Alice Loo、Danuta Lubicka、Kaitlin Macchi、Donald P. McDonnell、Yuji Mishina、John D. Norris、Jill Nunez、Chitra Saran、Yingchuan Sun、Noel M. Thomsen、Chunrong Wang、Jianling Wang、Stefan Peukert
DOI:10.1021/acs.jmedchem.6b01468
日期:2017.4.13
as a potent ERα 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
四氢异喹啉40已被确定为有效的ERα拮抗剂和选择性雌激素受体降解剂(SERD),在体内具有良好的口服生物利用度,抗肿瘤功效和SERD活性。我们概述了导致THIQ 40的THIQ支架的发现和化学优化,并展示了支架的消旋作用,临床前物种的药代动力学研究以及THIQ 40在MCF-7人乳腺癌异种移植模型中的体内功效。