Design and synthesis of poly ADP-ribose polymerase-1 inhibitors. 2. Biological evaluation of aza-5[H]-phenanthridin-6-ones as potent, aqueous-soluble compounds for the treatment of ischemic injuries

J Med Chem. 2003 Jul 3;46(14):3138-51. doi: 10.1021/jm030109s.

Abstract

A series of aza-5[H]-phenanthridin-6-ones were synthesized and evaluated as inhibitors of poly ADP-ribose polymerase-1 (PARP-1). Inhibitory potency of the unsubstituted aza-5[H]-phenanthridin-6-ones (i.e., benzonaphthyridones) was dependent on the position of the nitrogen atom within the core structure. The A ring nitrogen analogues (7-, 8-, and 10-aza-5[H]-phenanthridin-6-ones) were an order of magnitude less potent than C ring nitrogen analogues (1-, 2-, 3-, and 4-aza-5[H]-phenanthridin-6-ones). Preliminary stroke results from 1- and 2-aza-5[H]-phenanthridin-6-one prompted structure-activity relationships to be established for several 2- and 3-substituted 1-aza-5[H]-phenanthridin-6-ones. The 2-substituted 1-aza-5[H]-phenanthridin-6-ones were designed to improve the solubility and pharmacokinetic profiles for this series of PARP-1 inhibitors. Most importantly, three compounds from this series demonstrated statistically significant protective effects in rat models of stroke and heart ischemia.

MeSH terms

  • Animals
  • Aza Compounds / chemical synthesis*
  • Aza Compounds / chemistry
  • Aza Compounds / pharmacology
  • Brain Ischemia / drug therapy*
  • Dogs
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Haplorhini
  • Humans
  • In Vitro Techniques
  • Injections, Intravenous
  • Male
  • Microsomes, Liver / metabolism
  • Myocardial Ischemia / drug therapy*
  • Naphthyridines / chemical synthesis*
  • Naphthyridines / chemistry
  • Naphthyridines / pharmacology
  • Phenanthridines / chemical synthesis*
  • Phenanthridines / chemistry
  • Phenanthridines / pharmacology
  • Piperazines / chemical synthesis*
  • Piperazines / chemistry
  • Piperazines / pharmacology
  • Piperidines / chemical synthesis*
  • Piperidines / chemistry
  • Piperidines / pharmacology
  • Poly(ADP-ribose) Polymerase Inhibitors*
  • Rats
  • Rats, Sprague-Dawley
  • Rats, Wistar
  • Solubility
  • Structure-Activity Relationship
  • Tissue Distribution
  • Water

Substances

  • 2-(4-cyclopropylmethylpiperazin-1-yl)-5H-benzo(c)(1,5)naphthyridin-6-one
  • 2-(4-methylpiperazin-1-yl)-5H-benzo(c)(1,5)naphthyridin-6-one
  • Aza Compounds
  • Enzyme Inhibitors
  • N-(6-oxo-5,6-dihydrobenzo(c)(1,5)naphthyridin-2-yl)-2-(4-pyrrolidin-1-ylpiperidin-1-yl)acetamide
  • Naphthyridines
  • Phenanthridines
  • Piperazines
  • Piperidines
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Water