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
  • 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: [email protected].
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.