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
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Animals
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Aza Compounds / chemical synthesis*
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Aza Compounds / chemistry
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Aza Compounds / pharmacology
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Brain Ischemia / drug therapy*
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Dogs
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology
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Haplorhini
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Humans
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In Vitro Techniques
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Injections, Intravenous
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Male
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Microsomes, Liver / metabolism
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Myocardial Ischemia / drug therapy*
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Naphthyridines / chemical synthesis*
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Naphthyridines / chemistry
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Naphthyridines / pharmacology
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Phenanthridines / chemical synthesis*
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Phenanthridines / chemistry
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Phenanthridines / pharmacology
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Piperazines / chemical synthesis*
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Piperazines / chemistry
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Piperazines / pharmacology
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Piperidines / chemical synthesis*
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Piperidines / chemistry
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Piperidines / pharmacology
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Poly(ADP-ribose) Polymerase Inhibitors*
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Rats
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Rats, Sprague-Dawley
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Rats, Wistar
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Solubility
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Structure-Activity Relationship
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Tissue Distribution
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Water
Substances
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2-(4-cyclopropylmethylpiperazin-1-yl)-5H-benzo(c)(1,5)naphthyridin-6-one
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2-(4-methylpiperazin-1-yl)-5H-benzo(c)(1,5)naphthyridin-6-one
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Aza Compounds
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Enzyme Inhibitors
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N-(6-oxo-5,6-dihydrobenzo(c)(1,5)naphthyridin-2-yl)-2-(4-pyrrolidin-1-ylpiperidin-1-yl)acetamide
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Naphthyridines
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Phenanthridines
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Piperazines
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Piperidines
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Poly(ADP-ribose) Polymerase Inhibitors
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Water