Pyrrolidinones as potent functional antagonists of the human melanocortin-4 receptor

Wanlong Jiang; Fabio C Tucci; Joe A Tran; Beth A Fleck; Jenny Wen; Stacy Markison; Dragan Marinkovic; Caroline W Chen; Melissa Arellano; Sam R Hoare; Michael Johns; Alan C Foster; John Saunders; Chen Chen

doi:10.1016/j.bmcl.2007.07.097

Pyrrolidinones as potent functional antagonists of the human melanocortin-4 receptor

Bioorg Med Chem Lett. 2007 Oct 15;17(20):5610-3. doi: 10.1016/j.bmcl.2007.07.097. Epub 2007 Aug 23.

Authors

Wanlong Jiang¹, Fabio C Tucci, Joe A Tran, Beth A Fleck, Jenny Wen, Stacy Markison, Dragan Marinkovic, Caroline W Chen, Melissa Arellano, Sam R Hoare, Michael Johns, Alan C Foster, John Saunders, Chen Chen

Affiliation

¹ Department of Medicinal Chemistry, Neurocrine Biosciences, Inc., 12790 El Camino Real, San Diego, CA 92130, USA.

PMID: 17822895
DOI: 10.1016/j.bmcl.2007.07.097

Abstract

A series of pyrrolidinones derived from phenylalaninepiperazines were synthesized and characterized as potent and selective antagonists of the melanocortin-4 receptor. In addition to their high binding affinities, these compounds displayed high functional potencies. 12a had a K(i) of 0.94 nM in binding and IC(50) of 21 nM in functional activity. 12a also demonstrated efficacy in a mouse cachexia model.

MeSH terms

Alkylation
Amines / chemistry
Animals
Brain / drug effects
Humans
Ligands
Mice
Mice, Inbred C57BL
Molecular Structure
Pyrrolidinones / chemical synthesis
Pyrrolidinones / chemistry*
Pyrrolidinones / pharmacokinetics
Pyrrolidinones / pharmacology*
Receptor, Melanocortin, Type 4 / antagonists & inhibitors*
Receptor, Melanocortin, Type 4 / metabolism*
Structure-Activity Relationship

Substances

Amines
Ligands
MC4R protein, human
Pyrrolidinones
Receptor, Melanocortin, Type 4