Discovery of a C-8 hydroxychromene as a potent degrader of estrogen receptor alpha with improved rat oral exposure over GDC-0927.
- Resource Type
- Academic Journal
- Authors
- Labadie SS; Genentech Inc., South San Francisco, CA 94080, USA.; Li J; Genentech Inc., South San Francisco, CA 94080, USA.; Blake RA; Genentech Inc., South San Francisco, CA 94080, USA.; Chang JH; Genentech Inc., South San Francisco, CA 94080, USA.; Goodacre S; Charles River Laboratories, 7-9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom.; Hartman SJ; Genentech Inc., South San Francisco, CA 94080, USA.; Liang W; Genentech Inc., South San Francisco, CA 94080, USA.; Kiefer JR; Genentech Inc., South San Francisco, CA 94080, USA.; Kleinheinz T; Genentech Inc., South San Francisco, CA 94080, USA.; Lai T; WuXi AppTec Co., Ltd., Shanghai 200131, China.; Liao J; WuXi AppTec Co., Ltd., Shanghai 200131, China.; Ortwine DF; Genentech Inc., South San Francisco, CA 94080, USA.; Mody V; Genentech Inc., South San Francisco, CA 94080, USA.; Ray NC; Charles River Laboratories, 7-9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom.; Roussel F; Charles River Laboratories, 7-9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom.; Vinogradova M; Genentech Inc., South San Francisco, CA 94080, USA.; Yeap SK; Charles River Laboratories, 7-9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom.; Zhang B; Genentech Inc., South San Francisco, CA 94080, USA.; Zheng X; WuXi AppTec Co., Ltd., Shanghai 200131, China.; Zbieg JR; Genentech Inc., South San Francisco, CA 94080, USA.; Liang J; Genentech Inc., South San Francisco, CA 94080, USA.; Wang X; Genentech Inc., South San Francisco, CA 94080, USA. Electronic address: wang.xiaojing@gene.com.
- Source
- Publisher: Elsevier Science Ltd Country of Publication: England NLM ID: 9107377 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1464-3405 (Electronic) Linking ISSN: 0960894X NLM ISO Abbreviation: Bioorg Med Chem Lett Subsets: MEDLINE
- Subject
- Language
- English
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.
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