Tricyclic imidazole antagonists of the Neuropeptide S Receptor

B Wesley Trotter; Kausik K Nanda; Peter J Manley; Victor N Uebele; Cindra L Condra; Anthony L Gotter; Karsten Menzel; Martin Henault; Rino Stocco; John J Renger; George D Hartman; Mark T Bilodeau

doi:10.1016/j.bmcl.2010.04.016

Tricyclic imidazole antagonists of the Neuropeptide S Receptor

Bioorg Med Chem Lett. 2010 Aug 1;20(15):4704-8. doi: 10.1016/j.bmcl.2010.04.016. Epub 2010 Apr 13.

Authors

B Wesley Trotter¹, Kausik K Nanda, Peter J Manley, Victor N Uebele, Cindra L Condra, Anthony L Gotter, Karsten Menzel, Martin Henault, Rino Stocco, John J Renger, George D Hartman, Mark T Bilodeau

Affiliation

¹ Department of Medicinal Chemistry, Merck Research Laboratories, Boston, MA, USA. [email protected]

PMID: 20615693
DOI: 10.1016/j.bmcl.2010.04.016

Abstract

A new structural class of potent antagonists of the Neuropeptide S Receptor (NPSR) is reported. High-throughput screening identified a tricyclic imidazole antagonist of NPSR, and medicinal chemistry optimization of this structure was undertaken to improve potency against the receptor as well as CNS penetration. Detailed herein are synthetic and medicinal chemistry studies that led to the identification of antagonists 15 and NPSR-PI1, which demonstrate potent in vitro NPSR antagonism and central exposure in vivo.

MeSH terms

Animals
Heterocyclic Compounds, 3-Ring / chemical synthesis
Heterocyclic Compounds, 3-Ring / chemistry*
Heterocyclic Compounds, 3-Ring / pharmacology
High-Throughput Screening Assays
Humans
Imidazoles / chemical synthesis
Imidazoles / chemistry*
Imidazoles / pharmacology
Rats
Receptors, Neuropeptide / antagonists & inhibitors*
Receptors, Neuropeptide / metabolism
Structure-Activity Relationship

Substances

Heterocyclic Compounds, 3-Ring
Imidazoles
Receptors, Neuropeptide
imidazole