Stereoselective synthesis of a novel and bifunctional endothelin antagonist, IRL 3630

Bioorg Med Chem Lett. 1998 Aug 18;8(16):2247-52. doi: 10.1016/s0960-894x(98)00388-6.

Abstract

IRL 3630 (3), a single enantiomer of IRL 3461 with more potency was identified. Coupling reaction of the racemic fragment (1) with the chiral (L)-valinesulfonamide (2) under a biphasic solvent system (CH2Cl2-H2O) successfully led to the predominant formation of the desired isomer (3) with concomitant isomerization of 1. IRL 3630, N-butanesulfonyl-[N-(3,5-dimethylbenzoyl)-N-methyl-3-[4-(5-+ ++isoxazolyl) -phenyl]-(D)-alanyl]-(L)-valineamide, is a highly potent and bifunctional (ETA + ETB) antagonist [Ki(ETA) = 1.5 nM, Ki(ETB) = 1.2 nM].

MeSH terms

  • Animals
  • Biphenyl Compounds / chemical synthesis*
  • Biphenyl Compounds / chemistry
  • Biphenyl Compounds / pharmacology
  • Crystallography, X-Ray
  • Dipeptides / chemical synthesis*
  • Dipeptides / chemistry
  • Dipeptides / pharmacology
  • Endothelin Receptor Antagonists*
  • Indicators and Reagents
  • Kinetics
  • Models, Molecular
  • Molecular Conformation
  • Optical Rotation
  • Receptor, Endothelin A
  • Receptor, Endothelin B
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Biphenyl Compounds
  • Dipeptides
  • Endothelin Receptor Antagonists
  • Indicators and Reagents
  • Receptor, Endothelin A
  • Receptor, Endothelin B
  • IRL 3461