ERbeta ligands. 3. Exploiting two binding orientations of the 2-phenylnaphthalene scaffold to achieve ERbeta selectivity

• Published in: Journal of medicinal chemistry Vol. 48; no. 12; p. 3953
• Main Authors: Mewshaw, Richard E, Edsall, Jr, Richard J, Yang, Cuijian, Manas, Eric S, Xu, Zhang B, Henderson, Ruth A, Keith, Jr, James C, Harris, Heather A
• Format: Journal Article
• Language: English
• Published: United States 16.06.2005
• Subjects: Animals; Animals, Genetically Modified; Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis; Anti-Inflammatory Agents, Non-Steroidal - chemistry; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Arthritis, Experimental - drug therapy; Binding Sites; Cell Line, Tumor; Crystallography, X-Ray; Estrogen Receptor beta - agonists; Estrogen Receptor beta - chemistry; Female; Genistein - chemistry; Humans; Inflammatory Bowel Diseases - drug therapy; Ligands; Male; Models, Molecular; Molecular Conformation; Molecular Mimicry; Molecular Structure; Naphthalenes - chemical synthesis; Naphthalenes - chemistry; Naphthalenes - pharmacology; Naphthols - chemical synthesis; Naphthols - chemistry; Naphthols - pharmacology; Organ Size - drug effects; Rats; Rats, Inbred Lew; Structure-Activity Relationship; Transcription, Genetic - drug effects; Uterus - anatomy & histology; Uterus - drug effects
• ISSN: 0022-2623
• DOI: 10.1021/jm058173s

The 2-phenylnaphthalene scaffold was explored as a simplified version of genistein in order to identify ER selective ligands. With the aid of docking studies, positions 1, 4, and 8 of the 2-phenylnaphthalene template were predicted to be the most potentially influential positions to enhance ER selectivity using two different binding orientations. Both orientations have the phenol moiety mimicking the A-ring of genistein. Several compounds predicted to adopt orientations similar to that of genistein when bound to ERbeta were observed to have slightly higher ER affinity and selectivity than genistein. The second orientation we exploited, which was different from that of genistein when bound to ERbeta, resulted in the discovery of several compounds that had superior ER selectivity and affinity versus genistein. X-ray structures of two ER selective compounds (i.e., 15 and 47) confirmed the alternate binding mode and suggested that substituents at positions 1 and 8 were responsible for inducing selectivity. One compound (i.e., 47, WAY-202196) was further examined and found to be effective in two models of inflammation, suggesting that targeting ER may be therapeutically useful in treating certain chronic inflammatory diseases.