Discovery of a novel, potent and orally active series of γ-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 γ-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

Department of Chemistry and Chemical Biology

Merck

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

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 γ-lactam series of selective NK₁ antagonists. Optimization of the lactam series culminated in the identification of compounds with high binding affinity and excellent oral CNS activity.

Original language	English
Pages (from-to)	4168-4171
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	18
Issue number	14
DOIs	https://doi.org/10.1016/j.bmcl.2008.05.082
State	Published - 15 Jul 2008

Keywords

CNS
Emesis
Lactam
NK1
Substance P

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10.1016/j.bmcl.2008.05.082

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Paliwal, S., Reichard, G. A., Shah, S., Wrobleski, M. L., Wang, C., Stengone, C., Tsui, H. C., Xiao, D., Duffy, R. A., Lachowicz, J. E., Nomeir, A. A., Varty, G. B., & Shih, N. Y. (2008). Discovery of a novel, potent and orally active series of γ-lactams as selective NK₁ antagonists. Bioorganic and Medicinal Chemistry Letters, 18(14), 4168-4171. https://doi.org/10.1016/j.bmcl.2008.05.082

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title = "Discovery of a novel, potent and orally active series of γ-lactams as selective NK1 antagonists",

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 γ-lactam series of selective NK1 antagonists. Optimization of the lactam series culminated in the identification of compounds with high binding affinity and excellent oral CNS activity.",

keywords = "CNS, Emesis, Lactam, NK1, Substance P",

author = "Sunil Paliwal and Reichard, \{Gregory A.\} and Sapna Shah and Wrobleski, \{Michelle Laci\} and Cheng Wang and Carmine Stengone and Tsui, \{Hon Chung\} and Dong Xiao and Duffy, \{Ruth A.\} and Lachowicz, \{Jean E.\} and Nomeir, \{Amin A.\} and Varty, \{Geoffrey B.\} and Shih, \{Neng Yang\}",

year = "2008",

month = jul,

day = "15",

doi = "10.1016/j.bmcl.2008.05.082",

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Paliwal, S, Reichard, GA, Shah, S, Wrobleski, ML, Wang, C, Stengone, C, Tsui, HC, Xiao, D, Duffy, RA, Lachowicz, JE, Nomeir, AA, Varty, GB & Shih, NY 2008, 'Discovery of a novel, potent and orally active series of γ-lactams as selective NK₁ antagonists', Bioorganic and Medicinal Chemistry Letters, vol. 18, no. 14, pp. 4168-4171. https://doi.org/10.1016/j.bmcl.2008.05.082

TY - JOUR

T1 - Discovery of a novel, potent and orally active series of γ-lactams as selective NK1 antagonists

AU - Paliwal, Sunil

AU - Reichard, Gregory A.

AU - Shah, Sapna

AU - Wrobleski, Michelle Laci

AU - Wang, Cheng

AU - Stengone, Carmine

AU - Tsui, Hon Chung

AU - Xiao, Dong

AU - Duffy, Ruth A.

AU - Lachowicz, Jean E.

AU - Nomeir, Amin A.

AU - Varty, Geoffrey B.

AU - Shih, Neng Yang

PY - 2008/7/15

Y1 - 2008/7/15

N2 - 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 γ-lactam series of selective NK1 antagonists. Optimization of the lactam series culminated in the identification of compounds with high binding affinity and excellent oral CNS activity.

AB - 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 γ-lactam series of selective NK1 antagonists. Optimization of the lactam series culminated in the identification of compounds with high binding affinity and excellent oral CNS activity.

KW - CNS

KW - Emesis

KW - Lactam

KW - NK1

KW - Substance P

UR - https://www.scopus.com/pages/publications/47149088787

UR - https://www.scopus.com/pages/publications/47149088787#tab=citedBy

U2 - 10.1016/j.bmcl.2008.05.082

DO - 10.1016/j.bmcl.2008.05.082

M3 - Article

C2 - 18547807

AN - SCOPUS:47149088787

SN - 0960-894X

VL - 18

SP - 4168

EP - 4171

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 14

ER -

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

Abstract

Keywords

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