2. Academic Validation
  3. Discovery of a C-8 hydroxychromene as a potent degrader of estrogen receptor alpha with improved rat oral exposure over GDC-0927

Discovery of a C-8 hydroxychromene as a potent degrader of estrogen receptor alpha with improved rat oral exposure over GDC-0927

  • Bioorg Med Chem Lett. 2019 Aug 15;29(16):2090-2093. doi: 10.1016/j.bmcl.2019.07.013.
Sharada S Labadie 1,  Jun Li 1,  Robert A Blake 1,  Jae H Chang 1,  Simon Goodacre 2,  Steven J Hartman 1,  Weiling Liang 1,  James R Kiefer 1,  Tracy Kleinheinz 1,  Tommy Lai 3,  Jiangpeng Liao 3,  Daniel F Ortwine 1,  Vidhi Mody 1,  Nicholas C Ray 2,  Fabien Roussel 2,  Maia Vinogradova 1,  Siew Kuen Yeap 2,  Birong Zhang 1,  Xiaoping Zheng 3,  Jason R Zbieg 1,  Jun Liang 1,  Xiaojing Wang 4
Affiliations

Affiliations

  • 1 Genentech Inc., South San Francisco, CA 94080, USA.
  • 2 Charles River Laboratories, 7-9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom.
  • 3 WuXi AppTec Co., Ltd., Shanghai 200131, China.
  • 4 Genentech Inc., South San Francisco, CA 94080, USA. Electronic address: wang.xiaojing@gene.com.
PMID: 31311734 DOI: 10.1016/j.bmcl.2019.07.013
Abstract

Phenolic groups are responsible for the high clearance and low oral bioavailability of the Estrogen Receptor alpha (ERα) clinical candidate GDC-0927. An exhaustive search for a backup molecule with improved pharmacokinetic (PK) properties identified several metabolically stable analogs, although in general at the expense of the desired potency and degradation efficiency. C-8 hydroxychromene 30 is the first example of a phenol-containing chromene that not only maintained excellent potency but also exhibited 10-fold higher oral exposure in rats. The improved in vivo clearance in rat was hypothesized to be the result of C-8 hydroxy group being sterically protected from glucuronide conjugation. The excellent potency underscores the possibility of replacing the presumed indispensable phenolic group at C-6 or C-7 of the chromene core. Co-crystal structures were obtained to highlight the change in key interactions and rationalize the retained potency.

Keywords

Chromene; Degradation; Estrogen receptor; GDC-0927; Oral bioavailability.

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