Spiro-piperidine azetidinones as potent TRPV1 antagonists.
A series of spiro-piperidine azetidinone were synthesized and evaluated as potential TRPV1 antagonists. An important issue of plasma stability was investigated and resolved. Further focused SAR study lead to the discovery of a potent antagonist with good oral pharmacokinetic profile in rat.
Xiao
Dong
D
Chemical Research Department, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. dong.xiao@spcorp.com
Palani
Anandan
A
Aslanian
Robert
R
McKittrick
Brian A
BA
McPhail
Andrew T
AT
Correll
Craig C
CC
Phelps
P Tara
PT
Anthes
John C
JC
Rindgen
Diane
D
D000284:Administration, Oral; D000818:Animals; D001384:Azetidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D006863:Hydrogen-Ion Concentration; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D051381:Rats; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors*
C116379:2-azetidinone; D001384:Azetidines; D013141:Spiro Compounds; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human