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Beta 3 agonists. Part 1: evolution from inception to BMS-194449.
W N Washburn1, P M Sher, K M Poss
1Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 4000, Princeton, NJ 08543, USA. william.washburn@bms.com
Bioorganic & Medicinal Chemistry Letters
|November 21, 2001
Summary
Researchers identified novel compounds as beta 3 agonists. Modifications to these molecules enhanced selectivity for the beta 3 receptor, leading to the development of a promising clinical candidate for further study.
Area of Science:
- Medicinal Chemistry
- Pharmacology
Background:
- Beta 3 adrenergic receptors play a role in various physiological processes.
- Developing selective agonists for beta 3 receptors is a therapeutic goal.
Purpose of the Study:
- To identify and characterize novel beta 3 adrenergic receptor agonists.
- To explore structure-activity relationships (SAR) for optimizing beta 3 selectivity.
Main Methods:
- Screening of the BMS compound collection.
- Systematic chemical modification and SAR analysis of identified hit compounds.
- Evaluation of receptor binding and functional activity.
Main Results:
- 4-hydroxy-3-methylsulfonanilidoethanolamines were identified as full beta 3 agonists.
- Substitution on the ethanolamine nitrogen and C(alpha) positions modulated receptor selectivity.
- Highly selective beta 3 agonists, including 1,1-diarylmethylamines, were discovered.
Conclusions:
- Novel chemical scaffolds targeting beta 3 adrenergic receptors were developed.
- Structural modifications significantly improved beta 3 selectivity.
- A potent and selective beta 3 agonist, BMS-194449, was identified as a clinical candidate.
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