Design, stereoselective synthesis, and biological evaluation of novel tri-cyclic compounds as inhibitor of apoptosis proteins (IAP) antagonists

Bioorg Med Chem. 2013 Sep 15;21(18):5725-37. doi: 10.1016/j.bmc.2013.07.020. Epub 2013 Jul 18.

Abstract

We recently reported the discovery of octahydropyrrolo[1,2-a]pyrazine A as a lead compound for an inhibitor of apoptosis proteins (IAP) antagonist. To develop IAP antagonists with favorable PK profiles, we designed novel tri-cyclic compounds, octahydro-1H-cyclopropa[4,5]pyrrolo[1,2-a]pyrazines 1 and 2 based on co-crystal structural analysis of A with cellular IAP-1 (cIAP-1). The additional cyclopropane moiety was used to block the predicted metabolic site of compound A without detriment to the binding affinity for cIAP. Compounds 1 and 2 were stereoselectively synthesized via intermediates 4a and 5b', which were obtained by Simmons-Smith cyclopropanation of ethylester 3a and silyl ether 3b'. Compounds 1 and 2 showed strong growth inhibition in MDA-MB-231 breast cancer cells and improved metabolic stability in comparison to A. Compound 2 exhibited significant in vivo PD effects to increase tumor necrosis factor-alpha mRNA in a dose dependent manner.

Keywords: Inhibitor of apoptosis proteins (IAP); Octahydro-1H-cyclopropa[4,5]pyrrolo[1,2-a]pyrazine; Simmons−Smith cyclopropanation.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Benzopyrans / chemical synthesis
  • Benzopyrans / pharmacokinetics
  • Benzopyrans / therapeutic use
  • Binding Sites
  • Breast Neoplasms / drug therapy
  • Cell Line, Tumor
  • Crystallography, X-Ray
  • Drug Design*
  • Female
  • Half-Life
  • Humans
  • Inhibitor of Apoptosis Proteins / antagonists & inhibitors*
  • Inhibitor of Apoptosis Proteins / metabolism
  • Mice
  • Molecular Dynamics Simulation
  • Protein Structure, Tertiary
  • Pyrazines / chemical synthesis
  • Pyrazines / chemistry*
  • Pyrazines / pharmacokinetics
  • Pyrazines / therapeutic use
  • Pyrroles / chemical synthesis*
  • Pyrroles / chemistry
  • Pyrroles / pharmacokinetics
  • Pyrroles / therapeutic use
  • RNA, Messenger / metabolism
  • Stereoisomerism
  • Transplantation, Heterologous
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • (1aS,4S,6aR,7aS)-5-((2S)-2-cyclohexyl-2-((N-methyl-l-alanyl)amino)acetyl)-N-((4R)-3,4-dihydro-2H-chromen-4-yl)octahydro-1H-cyclopropa(4,5)pyrrolo(1,2-a)pyrazine-4-carboxamide dihydrochloride
  • Benzopyrans
  • Inhibitor of Apoptosis Proteins
  • Pyrazines
  • Pyrroles
  • RNA, Messenger
  • Tumor Necrosis Factor-alpha
  • octahydropyrrolo(1,2-a)pyrazine