Benzopyrans as selective estrogen receptor beta agonists (SERBAs). Part 5: Combined A- and C-ring structure-activity relationship studies

  • Bioorg Med Chem Lett. 2007 Oct 15;17(20):5563-6. doi: 10.1016/j.bmcl.2007.08.009.
Timothy I Richardson  1 ,  Jeffrey A Dodge ,  Yong Wang ,  Jim D Durbin ,  Venkatesh Krishnan ,  Bryan H Norman
Affiliations
  • 1. Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. [email protected]
PMID: 17804226 DOI: 10.1016/j.bmcl.2007.08.009
Abstract

Benzopyrans are selective Estrogen receptor (ER) beta agonists (SERBAs), which bind the ER subtypes alpha and beta in opposite orientations. Here we describe the synthesis of a late stage intermediate that allowed us to combine A-ring and C-ring modifications and carry out simultaneous SAR studies at both positions. Modification of both positions proved additive, maintaining affinity and improving ERbeta selectivity up to 83-fold. An X-ray cocrystal structure confirms the previously observed binding mode in ERbeta.

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