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Benzothiophene and naphthalene derived constrained SERMs.
Owen B Wallace1, Henry U Bryant, Pamela K Shetler
1Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. owen.wallace@lilly.com
Bioorganic & Medicinal Chemistry Letters
|September 24, 2004
Summary
The orientation of the basic side chain in selective estrogen receptor modulators (SERMs) significantly affects their function. Constraining the side chain
Area of Science:
- Medicinal Chemistry
- Endocrinology
- Pharmacology
Background:
- Selective estrogen receptor modulators (SERMs) are crucial therapeutics targeting estrogen receptor pathways.
- The spatial arrangement of the side chain in SERMs is known to influence their biological activity.
- Understanding structure-activity relationships is key to designing effective SERMs.
Purpose of the Study:
- To synthesize and evaluate novel SERM compounds with constrained side chain orientations.
- To investigate how defined side chain positioning impacts SERM function, particularly antagonism.
- To compare the biological profiles of SERMs with side chains in-plane versus pseudo-orthogonal to the core.
Main Methods:
- Chemical synthesis of two distinct series of SERM compounds.
- Biological evaluation of synthesized compounds.
- Assessment of estradiol antagonism on Ishikawa uterine cells.
Main Results:
- Successful synthesis of SERMs with controlled side chain orientations.
- Demonstrated differences in biological profiles based on side chain orientation.
- Specific differences observed in the antagonism of estradiol action in Ishikawa cells.
Conclusions:
- The orientation of the basic side chain is a critical determinant of SERM activity.
- Constrained side chain positioning can lead to distinct functional profiles, including differential antagonism.
- These findings provide valuable insights for the rational design of next-generation SERMs.