Novel 2-aminooctahydrocyclopentalene-3a-carboxamides as potent CCR2 antagonists

Bioorg Med Chem Lett. 2013 Jan 1;23(1):351-4. doi: 10.1016/j.bmcl.2012.10.069. Epub 2012 Oct 24.

Abstract

Novel CCR2 antagonists with a novel 2-aminooctahydrocyclopentalene-3a-carboxamide scaffold were designed. SAR studies led to a series of potent compounds. For example, compound 51 had a good PK profile in both dog and monkey, and exhibited excellent efficacy when dosed orally in an inflammation model in hCCR2 KI mice. In addition, an asymmetric synthesis to the core structures was developed.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Amides / chemistry*
  • Amides / pharmacokinetics
  • Amides / therapeutic use
  • Animals
  • Bridged Bicyclo Compounds, Heterocyclic / chemistry*
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacokinetics
  • Bridged Bicyclo Compounds, Heterocyclic / therapeutic use
  • Cyclopentanes / chemistry*
  • Disease Models, Animal
  • Dogs
  • Half-Life
  • Haplorhini
  • Humans
  • Inflammation / drug therapy
  • Mice
  • Mice, Knockout
  • Protein Binding
  • Pyridines / chemistry*
  • Pyridines / pharmacokinetics
  • Pyridines / therapeutic use
  • Receptors, CCR2 / antagonists & inhibitors*
  • Receptors, CCR2 / genetics
  • Receptors, CCR2 / metabolism
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Amides
  • Bridged Bicyclo Compounds, Heterocyclic
  • Cyclopentanes
  • Pyridines
  • Receptors, CCR2
  • pentalenene