Aza-bicyclic Amino Acid Carboxamides as alpha4beta1/alpha4beta7 Integrin Receptor Antagonists

Bioorg Med Chem. 2005 Dec 15;13(24):6693-702. doi: 10.1016/j.bmc.2005.07.022. Epub 2005 Aug 19.

Abstract

A series of N-carboxy, N-alkyl, and N-carboxamido azabicyclo[2.2.2]octane carboxamides were prepared and assayed for inhibition of alpha4beta1-VCAM-1 and alpha4beta7-MAdCAM-1 interactions. Potency and alpha4beta1/alpha4beta7 selectivity were sensitive to the substituent R1-R3 in the structures 6, 7, and 8. Several compounds demonstrated low nanomolar balanced alpha4beta1/alpha4beta7 in vitro activity. Two compounds were selected for in vivo leukocytosis studies and demonstrated increases in circulating lymphocytes up to 250% over control.

MeSH terms

  • Amino Acids, Cyclic / chemistry*
  • Animals
  • Aza Compounds / chemical synthesis*
  • Aza Compounds / chemistry
  • Aza Compounds / pharmacology*
  • Female
  • Integrin alpha4beta1 / antagonists & inhibitors*
  • Integrin alpha4beta1 / metabolism
  • Integrins / antagonists & inhibitors*
  • Integrins / metabolism
  • Leukocytosis
  • Lymphocytes / drug effects
  • Male
  • Mice
  • Molecular Structure
  • Rats
  • Structure-Activity Relationship

Substances

  • Amino Acids, Cyclic
  • Aza Compounds
  • Integrin alpha4beta1
  • Integrins
  • integrin alpha4beta7