Discovery of a novel, potent and orally active series of gamma-lactams as selective NK1 antagonists

Sunil Paliwal; Gregory A Reichard; Sapna Shah; Michelle Laci Wrobleski; Cheng Wang; Carmine Stengone; Hon-Chung Tsui; Dong Xiao; Ruth A Duffy; Jean E Lachowicz; Amin A Nomeir; Geoffrey B Varty; Neng-Yang Shih

doi:10.1016/j.bmcl.2008.05.082

Discovery of a novel, potent and orally active series of gamma-lactams as selective NK1 antagonists

Bioorg Med Chem Lett. 2008 Jul 15;18(14):4168-71. doi: 10.1016/j.bmcl.2008.05.082. Epub 2008 May 24.

Authors

Sunil Paliwal¹, Gregory A Reichard, Sapna Shah, Michelle Laci Wrobleski, Cheng Wang, Carmine Stengone, Hon-Chung Tsui, Dong Xiao, Ruth A Duffy, Jean E Lachowicz, Amin A Nomeir, Geoffrey B Varty, Neng-Yang Shih

Affiliation

¹ Chemical Research Department, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. [email protected]

PMID: 18547807
DOI: 10.1016/j.bmcl.2008.05.082

Abstract

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.

MeSH terms

Administration, Oral
Chemistry, Pharmaceutical / methods
Drug Design
Humans
Lactams / chemistry*
Models, Chemical
Molecular Structure
Neurokinin-1 Receptor Antagonists*
Nitrogen / chemistry
Protein Binding
Receptors, Neurokinin-1 / chemistry*
Structure-Activity Relationship
Substance P / chemistry
Urea / chemistry
Vomiting

Substances

Lactams
Neurokinin-1 Receptor Antagonists
Receptors, Neurokinin-1
Substance P
Urea
Nitrogen