Nonpeptide alpha(v)beta(3) antagonists. 1. Transformation of a potent, integrin-selective alpha(IIb)beta(3) antagonist into a potent alpha(v)beta(3) antagonist

J Med Chem. 2000 Oct 5;43(20):3736-45. doi: 10.1021/jm000133v.

Abstract

Modification of the potent fibrinogen receptor (alpha(IIb)beta(3)) antagonist 1 generated compounds with high affinity for the vitronectin receptor alpha(v)beta(3). Sequential modification of the basic N-terminus of 1 led to the identification of the 5,6,7, 8-tetrahydro[1,8]naphthyridine moiety (THN) as a lipophilic, moderately basic N-terminus that provides molecules with excellent potency and selectivity for the integrin receptor alpha(v)beta(3). The THN-containing analogue 5 is a potent inhibitor of bone resorption in vitro and in vivo. In addition, the identification of a novel, nonpeptide radioligand with high affinity to alpha(v)beta(3) is also reported.

MeSH terms

  • Animals
  • Bone Resorption / pathology
  • Cell Line
  • Culture Techniques
  • Humans
  • Ligands
  • Naphthyridines / chemical synthesis*
  • Naphthyridines / chemistry
  • Naphthyridines / pharmacology
  • Platelet Aggregation / drug effects
  • Platelet Glycoprotein GPIIb-IIIa Complex / antagonists & inhibitors*
  • Propionates / chemical synthesis*
  • Propionates / chemistry
  • Propionates / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Sulfonamides / chemical synthesis*
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology

Substances

  • 2-benzenesulfonylamino-3-(4-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)benzoylamino)propionic acid
  • Ligands
  • Naphthyridines
  • Platelet Glycoprotein GPIIb-IIIa Complex
  • Propionates
  • Sulfonamides