Discovery of a novel, potent and orally active series of gamma-lactams as selective NK1 antagonists.
Strategic replacement of the nitrogen of the lead compound 1 in the original cyclic urea series with a carbon resulted in the discovery of a novel, potent and orally more efficacious gamma-lactam series of selective NK(1) antagonists. Optimization of the lactam series culminated in the identification of compounds with high binding affinity and excellent oral CNS activity.
Paliwal
Sunil
S
Chemical Research Department, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. sunil.paliwal@spcorp.com
Reichard
Gregory A
GA
Shah
Sapna
S
Wrobleski
Michelle Laci
ML
Wang
Cheng
C
Stengone
Carmine
C
Tsui
Hon-Chung
HC
Xiao
Dong
D
Duffy
Ruth A
RA
Lachowicz
Jean E
JE
Nomeir
Amin A
AA
Varty
Geoffrey B
GB
Shih
Neng-Yang
NY
D000284:Administration, Oral; D002626:Chemistry, Pharmaceutical / Q000379:methods; D015195:Drug Design; D006801:Humans; D007769:Lactams / Q000737:chemistry*; D008956:Models, Chemical; D015394:Molecular Structure; D064729:Neurokinin-1 Receptor Antagonists; D009584:Nitrogen / Q000737:chemistry; D011485:Protein Binding; D018040:Receptors, Neurokinin-1 / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013373:Substance P / Q000737:chemistry; D014508:Urea / Q000737:chemistry; D014839:Vomiting
D007769:Lactams; D064729:Neurokinin-1 Receptor Antagonists; D018040:Receptors, Neurokinin-1; D013373:Substance P; D014508:Urea; D009584:Nitrogen