Azepinone as a conformational constraint in the design of kappa-opioid receptor agonists

Paul A Tuthill; Pamela R Seida; William Barker; Joel A Cassel; Serge Belanger; Robert N DeHaven; Michael Koblish; Susan L Gottshall; Patrick J Little; Diane L DeHaven-Hudkins; Roland E Dolle

doi:10.1016/j.bmcl.2004.08.041

Azepinone as a conformational constraint in the design of kappa-opioid receptor agonists

Bioorg Med Chem Lett. 2004 Nov 15;14(22):5693-7. doi: 10.1016/j.bmcl.2004.08.041.

Authors

Paul A Tuthill¹, Pamela R Seida, William Barker, Joel A Cassel, Serge Belanger, Robert N DeHaven, Michael Koblish, Susan L Gottshall, Patrick J Little, Diane L DeHaven-Hudkins, Roland E Dolle

Affiliation

¹ Department of Chemistry, Adolor Corporation, 700 Pennsylvania Drive, Exton, PA 19341, USA.

PMID: 15482950
DOI: 10.1016/j.bmcl.2004.08.041

Abstract

A new class of kappa-opioid receptor agonists is described. The design of these agents was based upon energy minimization and structural overlay studies of the generic azepin-2-one structure 3 with the crystal structure of arylacetamide kappa agonist 1, ICI 199441. The most active compound identified was ligand 4a (K(i)=0.34 nM), which demonstrated potent antinociceptive activity after oral administration in rodents.

MeSH terms

Acetic Acid / chemistry
Animals
Azepines / chemical synthesis
Azepines / chemistry*
Azepines / pharmacology
Binding Sites
Drug Design
Formaldehyde / chemistry
Ligands
Mice
Models, Molecular
Molecular Conformation
Pain Measurement / drug effects
Rats
Receptors, Opioid, kappa / agonists*
Stereoisomerism
Structure-Activity Relationship

Substances

Azepines
Ligands
Receptors, Opioid, kappa
Formaldehyde
Acetic Acid