Discovery of 1-[2-[(1S)-(3-dimethylaminopropionyl)amino-2-methylpropyl]-4-methylphenyl]-4-[(2R)-methyl-3-(4-chlorophenyl)-propionyl]piperazine as an orally active antagonist of the melanocortin-4 receptor for the potential treatment of cachexia

J Med Chem. 2007 Nov 1;50(22):5249-52. doi: 10.1021/jm070806a. Epub 2007 Oct 5.

Abstract

A potent and selective antagonist of the melanocortin-4 receptor, 1-[2-[(1S)-(3-dimethylaminopropionyl)amino-2-methylpropyl]-6-methylphenyl]-4-[(2R)-methyl-3-(4-chlorophenyl)propionyl]piperazine (10d), was identified from a series piperazinebenzylamine attached with a N,N-dimethyl-beta-alanine side chain. This compound possessed high water solubility and exhibited good metabolic profiles. In animals, 10d showed moderate to good oral bioavailability and promoted food intake in tumor-bearing mice after oral administration.

Publication types

  • Comparative Study

MeSH terms

  • Administration, Oral
  • Animals
  • Biological Availability
  • Cachexia / drug therapy*
  • Cachexia / etiology
  • Cyclic AMP / metabolism
  • Dogs
  • Eating / drug effects
  • Humans
  • Macaca mulatta
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Microsomes, Liver / metabolism
  • Neoplasm Transplantation
  • Neoplasms, Experimental / complications
  • Piperazines / chemical synthesis*
  • Piperazines / pharmacokinetics
  • Piperazines / pharmacology
  • Radioligand Assay
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Melanocortin, Type 4 / antagonists & inhibitors*
  • Solubility
  • Stereoisomerism
  • Structure-Activity Relationship
  • beta-Alanine / analogs & derivatives*
  • beta-Alanine / chemical synthesis
  • beta-Alanine / pharmacokinetics
  • beta-Alanine / pharmacology

Substances

  • 1-(2-(1-(3-dimethylaminopropionyl)amino-2-methylpropyl)-4-methylphenyl)-4-(2-methyl-3-(4-chlorophenyl)propionyl)piperazine
  • Piperazines
  • Receptor, Melanocortin, Type 4
  • beta-Alanine
  • Cyclic AMP