Design, synthesis, and evaluation of conformationally restricted acetanilides as potent and selective β3 adrenergic receptor agonists for the treatment of overactive bladder.

Abstract

A series of conformationally restricted acetanilides were synthesized and evaluated as β3-adrenergic receptor agonists (β3-AR) for the treatment of overactive bladder (OAB). Optimization studies identified a five-membered ring as the preferred conformational lock of the acetanilide. Further optimization of both the aromatic and thiazole regions led to compounds such as 19 and 29, which have a good balance of potency and selectivity. These compounds have significantly reduced intrinsic clearance compared to our initial series of pyridylethanolamine β3-AR agonists and thus have improved unbound drug exposures. Both analogues demonstrated dose dependent β3-AR mediated responses in a rat bladder hyperactivity model.

• Authors: Christopher R Moyes, Richard Berger, Stephen D Goble, Bart Harper, Dong-Ming Shen, Liping Wang, Alka Bansal, Patricia N Brown, Airu S Chen, Karen H Dingley, Jerry Di Salvo, Aileen Fitzmaurice, Loise N Gichuru, Amanda L Hurley, Nina Jochnowitz, Randall R Miller, Shruty Mistry, Hiroshi Nagabukuro, Gino M Salituro, Anthony Sanfiz, Andra S Stevenson, Katherine Villa, Beata Zamlynny, Mary Struthers, Ann E Weber, Scott D Edmondson
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 57 Issue 4 Pg. 1437-53 (Feb 27 2014) ISSN: 1520-4804 [Electronic] United States
• PMID: 24437735 (Publication Type: Journal Article)

Chemical References

• Acetanilides
• Adrenergic beta-3 Receptor Agonists

Topics

• Acetanilides (chemical synthesis, pharmacology, therapeutic use)
• Adrenergic beta-3 Receptor Agonists (chemical synthesis, pharmacology, therapeutic use)
• Animals
• CHO Cells
• Cricetinae
• Cricetulus
• Drug Design
• Humans
• Magnetic Resonance Spectroscopy
• Molecular Conformation
• Urinary Bladder, Overactive (drug therapy)