Novel sulfamoyl benzamides as selective CB(2) agonists with improved in vitro metabolic stability.
A lead optimization campaign in our previously reported sulfamoyl benzamide class of CB(2) agonists was conducted to improve the in vitro metabolic stability profile in this series while retaining high potency and selectivity for the CB(2) receptor. From this study, compound 14, N-(3,4-dimethyl-5-(morpholinosulfonyl)phenyl)-2,2-dimethylbutanamide, was identified as a potent and selective CB(2) agonist exhibiting moderate in vitro metabolic stability and oral bioavailability. Compound 14 demonstrated in vivo efficacy in a rat model of post-surgical pain.
Sellitto
Ian
I
Department of Chemistry, Adolor Corporation, 700 Pennsylvania Drive, Exton, PA 19341, USA.
Le Bourdonnec
Bertrand
B
Worm
Karin
K
Goodman
Allan
A
Savolainen
Markku A
MA
Chu
Guo-Hua
GH
Ajello
Christopher W
CW
Saeui
Christopher T
CT
Leister
Lara K
LK
Cassel
Joel A
JA
Dehaven
Robert N
RN
Labuda
Christopher J
CJ
Koblish
Michael
M
Little
Patrick J
PJ
Brogdon
Bernice L
BL
Smith
Steven A
SA
Dolle
Roland E
RE
D000814:Aniline Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D010146:Pain / Q000188:drug therapy; D051381:Rats; D017207:Rats, Sprague-Dawley; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics
D000814:Aniline Compounds; D001549:Benzamides; C549139:N-(3,4-dimethyl-5-(morpholinosulfonyl)phenyl)-2,2-dimethylbutanamide; D043885:Receptor, Cannabinoid, CB2; D013449:Sulfonamides