title: Design and synthesis of poly(ADP-ribose)polymerase-1 (PARP-1) inhibitors. Part 3: In vitro evaluation of 1,3,4,5-tetrahydro-benzo[c][1,6]- and [c][1,7]-naphthyridin-6-ones.
abstract: The 1,3,4,5-tetrahydro-benzo[c][1,6]- and [c][1,7]-napthyridin-6-ones are presented as a potent class of PARP-1 inhibitors. Derivatives of these partially saturated aza-5[H]-phenanthridin-6-ones were designed and synthesized with tertiary amines for salt formation, thus enhancing aqueous solubility, iv formulation and their potential use in acute ischemic injuries (i.e., myocardial ischemia and stroke). We found that partial saturation of the C-ring results in derivatives that are several times more potent than the aromatic C-ring derivatives. The general synthetic routes are presented herein as well as thorough in vitro potencies and SAR discussion for selected derivatives.
authors.affiliation: Guilford Pharmaceuticals Inc., 6611 Tributary Street, Baltimore, MA 21224, USA. ferrarisd@guilfordpharm.com
authors.forename: Dana
authors.initials: D
authors.lastname: Ferraris
authors.forename: Rica Pargas
authors.initials: RP
authors.lastname: Ficco
authors.forename: Thomas
authors.initials: T
authors.lastname: Pahutski
authors.forename: Susan
authors.initials: S
authors.lastname: Lautar
authors.forename: Shirley
authors.initials: S
authors.lastname: Huang
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.forename: Vincent
authors.initials: V
authors.lastname: Kalish
mesh_terms: D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D007202:Indicators and Reagents; D009287:Naphthyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: C482463:1,3,4,5-tetrahydro-benzo(c)(1,6)-napthyridin-6-one; C482464:1,3,4,5-tetrahydro-benzo(c)(1,7)-napthyridin-6-one; D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D009287:Naphthyridines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors