Design, synthesis, and evaluation of conformationally restricted acetanilides as potent and selective β3 adrenergic receptor agonists for the treatment of overactive bladder.
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.
Early Development and Discovery Sciences, Merck and Co., Inc. , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
Christopher R
CR
Moyes
Richard
R
Berger
Stephen D
SD
Goble
Bart
B
Harper
Dong-Ming
DM
Shen
Liping
L
Wang
Alka
A
Bansal
Patricia N
PN
Brown
Airu S
AS
Chen
Karen H
KH
Dingley
Jerry
J
Di Salvo
Aileen
A
Fitzmaurice
Loise N
LN
Gichuru
Amanda L
AL
Hurley
Nina
N
Jochnowitz
Randall R
RR
Miller
Shruty
S
Mistry
Hiroshi
H
Nagabukuro
Gino M
GM
Salituro
Anthony
A
Sanfiz
Andra S
AS
Stevenson
Katherine
K
Villa
Beata
B
Zamlynny
Mary
M
Struthers
Ann E
AE
Weber
Scott D
SD
Edmondson
D000083:Acetanilides / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use; D058667:Adrenergic beta-3 Receptor Agonists / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D015195:Drug Design; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D053201:Urinary Bladder, Overactive / Q000188:drug therapy*
D000083:Acetanilides; D058667:Adrenergic beta-3 Receptor Agonists