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.
Chemical Research Department, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. sunil.paliwal@spcorp.com
Sunil
S
Paliwal
Gregory A
GA
Reichard
Sapna
S
Shah
Michelle Laci
ML
Wrobleski
Cheng
C
Wang
Carmine
C
Stengone
Hon-Chung
HC
Tsui
Dong
D
Xiao
Ruth A
RA
Duffy
Jean E
JE
Lachowicz
Amin A
AA
Nomeir
Geoffrey B
GB
Varty
Neng-Yang
NY
Shih
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