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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.

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Fused pyridine derivativesFused pyridine derivatives R 0450Design and Synthesis of Poly(ADP-ribose)polymerase-1 (PARP-1) Inhibitors. Part In vitro Evaluation of 1,3,4,5-Tetrahydro-benzo[c][1,6]-and [c][1,7]-naphthyri-din-6-ones. -Design, synthesis and in vitro activities of the title benzonaphthyridines (VIII) and (XV), resp., as well as corresponding aminoacylated products [cf. (IX)] as PARP-1 inhibitors are reported. -(FERRARIS*, D.; FICCO, R. P.; PAHUTSKI, T.; LAUTAR, S.; HUANG, S.; ZHANG, J.; KALISH, V.; Bioorg. Med. Chem. Lett. 13 (2003) 15, 2513-2518; Dep. Res., Guilford Pharm., Inc., Baltimore, MD 21224, USA; Eng.) -M. Schroeter 44-132 2003 Fused pyridine derivatives