Discovery of a C-8 hydroxychromene as a potent degrader of estrogen receptor alpha with improved rat oral exposure over GDC-0927. Issue 16 (15th August 2019)

• Record Type: Journal Article
• 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
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 29:Issue 16(2019)
• Page Start: 2090
• Page End: 2093
• Publication Date: 2019-08-15
• Subjects: Estrogen receptor -- GDC-0927 -- Chromene -- Oral bioavailability -- Degradation; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2019.07.013
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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.