Luck be a lady tonight: Generation of a new SERM template from an Estrogen Related Receptor Gamma (ERRg) program

COMP 9

Aaron B. Miller1, Adwoa Akwabi-Ameyaw, adwoa.a.akwabi-ameyaw@gsk.com2, Jing Fang2, David Gray3, Dennis Heyer2, Subba R. Katamreddy2, Kevin Madauss4, Lisa A. Orband-Miller1, Wendy Y. Mills2, Frank Navas III2, Robert T. Nolte1, Rosemary Sasse3, Terrence L. Smalley Jr.2, Liping Wang1, Shawn Williams4, and William J. Zuercher, william.j.zuercher@gsk.com1. (1) Discovery Research, GlaxoSmithKline, Five Moore Drive, Research Triangle Park, NC 27709, (2) Department of Medicinal Chemistry, MV CEDD, GlaxoSmithKline, Five Moore Drive, Research Triangle Park, NC 27709-3398, (3) Discovery Research, Screening and Compound Profiling, GlaxoSmithKline, Stevenage, United Kingdom, (4) Discovery Research, CASS, GlaxoSmithKline, Five Moore Drive, Research Triangle Park, NC 27709
Estrogen Related Receptors (ERRs) are orphan nuclear receptors that are similar to the Estrogen Receptors (ERs). 4-Hydroxy-Tamoxifen (4OH-TAMOX) is an inverse agonist of the ERR gamma receptor subtype (ERRg). Using an in-house ERRg /4OH-TAMOX co-crystal structure with the hopes of getting selective compounds for ERRg, a new series of “cyclic alkylidenes” were synthesized. Although the series did have affinity to the ERRg receptor, they did not fulfill the desired selectivity profile. However, this template did offer a novel series for the design of new ER modulators. The in vitro SAR as well as X-ray co-crystal structures for a subset of these cyclic alkylidenes will be discussed.
 

Structure-Based Design & Development of Estrogen Receptor Modulators
9:00 AM-12:35 PM, Sunday, 10 September 2006 Moscone Center -- Room 224/226, Oral

Division of Computers in Chemistry

The 232nd ACS National Meeting, San Francisco, CA, September 10-14, 2006