Convergent synthesis of complex diketopiperazines derived from pipecolic acid scaffolds and parallel screening against GPCR targets

J Org Chem. 2006 Nov 10;71(23):8934-45. doi: 10.1021/jo061758p.

Abstract

A convergent approach to highly functionalized diketopiperazines (DKPs) using enantioenriched pipecolic acids is described. Scandium triflate-catalyzed [4 + 2] aza-annulation was employed to produce stereochemically well-defined building blocks. A resin "catch and release" strategy was devised to convert annulation products to pipecolic acid monomers. Complex diketopiperazines were efficiently assembled utilizing one-pot cyclodimerization of pipecolic acids. Massively parallel screening of the complex DKPs against a panel of molecular targets identified novel ligands for a number of G-protein-coupled receptors (GPCRs).

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aza Compounds / chemical synthesis
  • Aza Compounds / chemistry
  • Catalysis
  • Combinatorial Chemistry Techniques / methods*
  • Crystallography, X-Ray
  • Diketopiperazines
  • Drug Evaluation, Preclinical
  • Models, Molecular
  • Molecular Conformation
  • Pipecolic Acids / chemistry*
  • Piperazines / chemical synthesis*
  • Piperazines / chemistry
  • Piperazines / pharmacology*
  • Receptors, G-Protein-Coupled / antagonists & inhibitors*
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Aza Compounds
  • Diketopiperazines
  • Pipecolic Acids
  • Piperazines
  • Receptors, G-Protein-Coupled
  • pipecolic acid