title: 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.
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.
authors.affiliation: Guilford Pharmaceuticals Inc, 6611 Tributary Street, Baltimore, Maryland 21224, USA. ferraisd@guildfordpharm.com
authors.forename: Dana
authors.initials: D
authors.lastname: Ferraris
authors.forename: Yao-Sen
authors.initials: YS
authors.lastname: Ko
authors.forename: Thomas
authors.initials: T
authors.lastname: Pahutski
authors.forename: Rica Pargas
authors.initials: RP
authors.lastname: Ficco
authors.forename: Larisa
authors.initials: L
authors.lastname: Serdyuk
authors.forename: Christina
authors.initials: C
authors.lastname: Alemu
authors.forename: Chadwick
authors.initials: C
authors.lastname: Bradford
authors.forename: Tiffany
authors.initials: T
authors.lastname: Chiou
authors.forename: Randall
authors.initials: R
authors.lastname: Hoover
authors.forename: Shirley
authors.initials: S
authors.lastname: Huang
authors.forename: Susan
authors.initials: S
authors.lastname: Lautar
authors.forename: Shi
authors.initials: S
authors.lastname: Liang
authors.forename: Qian
authors.initials: Q
authors.lastname: Lin
authors.forename: May X-C
authors.initials: MX
authors.lastname: Lu
authors.forename: Maria
authors.initials: M
authors.lastname: Mooney
authors.forename: Lisa
authors.initials: L
authors.lastname: Morgan
authors.forename: Yongzhen
authors.initials: Y
authors.lastname: Qian
authors.forename: Scott
authors.initials: S
authors.lastname: Tran
authors.forename: Lawrence R
authors.initials: LR
authors.lastname: Williams
authors.forename: Qi Yi
authors.initials: QY
authors.lastname: Wu
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.forename: Yinong
authors.initials: Y
authors.lastname: Zou
authors.forename: Vincent
authors.initials: V
authors.lastname: Kalish
mesh_terms: D000818:Animals; D001372:Aza Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002545:Brain Ischemia / Q000188:drug therapy*; D004285:Dogs; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000882:Haplorhini; D006801:Humans; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D017202:Myocardial Ischemia / Q000188:drug therapy*; D009287:Naphthyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010617:Phenanthridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D012995:Solubility; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D014867:Water
chemical_list: C476144:2-(4-cyclopropylmethylpiperazin-1-yl)-5H-benzo(c)(1,5)naphthyridin-6-one; C476143:2-(4-methylpiperazin-1-yl)-5H-benzo(c)(1,5)naphthyridin-6-one; D001372:Aza Compounds; D004791:Enzyme Inhibitors; C476145:N-(6-oxo-5,6-dihydrobenzo(c)(1,5)naphthyridin-2-yl)-2-(4-pyrrolidin-1-ylpiperidin-1-yl)acetamide; D009287:Naphthyridines; D010617:Phenanthridines; D010879:Piperazines; D010880:Piperidines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D014867:Water