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

[Display omitted] 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 ana...

Full description

Saved in:
Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2019-08, Vol.29 (16), p.2090-2093
Main Authors: Labadie, Sharada S., Li, Jun, Blake, Robert A., Chang, Jae H., Goodacre, Simon, Hartman, Steven J., Liang, Weiling, Kiefer, James R., Kleinheinz, Tracy, Lai, Tommy, Liao, Jiangpeng, Ortwine, Daniel F., Mody, Vidhi, Ray, Nicholas C., Roussel, Fabien, Vinogradova, Maia, Yeap, Siew Kuen, Zhang, Birong, Zheng, Xiaoping, Zbieg, Jason R., Liang, Jun, Wang, Xiaojing
Format: Article
Language:English
Subjects:
Chromene
Degradation
Estrogen receptor
GDC-0927
Oral bioavailability
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:[Display omitted] 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.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2019.07.013