Design, synthesis, and evaluation of conformationally restricted acetanilides as potent and selective ß3 adrenergic receptor agonists for the treatment of overactive bladder.
J Med Chem
; 57(4): 1437-53, 2014 Feb 27.
Article
in En
| MEDLINE
| ID: mdl-24437735
ABSTRACT
A series of conformationally restricted acetanilides were synthesized and evaluated as ß3-adrenergic receptor agonists (ß3-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 ß3-AR agonists and thus have improved unbound drug exposures. Both analogues demonstrated dose dependent ß3-AR mediated responses in a rat bladder hyperactivity model.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Urinary Bladder, Overactive
/
Adrenergic beta-3 Receptor Agonists
/
Acetanilides
Limits:
Animals
/
Humans
Language:
En
Journal:
J Med Chem
Journal subject:
QUIMICA
Year:
2014
Document type:
Article
Affiliation country: