Isoxazolyl, oxazolyl, and thiazolylpropionic acid derivatives as potent alpha(4)beta(1) integrin antagonists

Bioorg Med Chem Lett. 2001 Oct 8;11(19):2593-6. doi: 10.1016/s0960-894x(01)00511-x.

Abstract

A series of isoxazolyl, oxazolyl, and thiazolylpropionic acid derivatives derived from LDV was found to be a potent antagonist of the alpha(4)beta(1) integrin. The synthesis and SAR leading up to 3-[3-(1-[-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino]-3-methyl-butyl)-isoxazol-5-yl]-propionic acid (22) are reported. In an allergic mouse model, compound 22 was efficacious delivered systemically (58% inhib @ 10 mg/kg, sc) as well as by intra-tracheal instillation (ED(50)=2 microg/kg).

MeSH terms

  • Animals
  • Disease Models, Animal
  • Humans
  • Hypersensitivity / drug therapy
  • Integrin alpha4beta1
  • Integrins / antagonists & inhibitors*
  • Isoxazoles / pharmacology*
  • Jurkat Cells
  • Mice
  • Propionates / pharmacology*
  • Receptors, Lymphocyte Homing / antagonists & inhibitors*
  • Structure-Activity Relationship

Substances

  • 3-(3-(1-(-(3-methoxy-4-(3-o-tolyl-ureido)-phenyl)-acetylamino)-3-methyl-butyl)-isoxazol-5-yl)-propionic acid
  • Integrin alpha4beta1
  • Integrins
  • Isoxazoles
  • Propionates
  • Receptors, Lymphocyte Homing