title: Design and synthesis of poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors. Part 4: biological evaluation of imidazobenzodiazepines as potent PARP-1 inhibitors for treatment of ischemic injuries.
abstract: A class of poly(ADP-ribose) polymerase (PARP-1) inhibitors, the imidazobenzodiazepines, are presented in this text. Several derivatives were designed and synthesized with ionizable groups (i.e., tertiary amines) in order to promote the desired pharmaceutical characteristics for administration in ischemic injury. Within this series, several compounds have excellent in vitro potency and our computational models accurately justify the structure-activity relationships (SARs) and highlight essential hydrogen bonding residues and hydrophobic pockets within the catalytic domain of PARP-1. Administration of these compounds (5q, 17a and 17e) in the mouse model of streptozotocin-induced diabetes results in maintainance of glucose levels. Furthermore, one such inhibitor (5g, IC(50)=26 nM) demonstrated significant reduction of infarct volume in the rat model of permanent focal cerebral ischemia.
authors.affiliation: Guilford Pharmaceuticals Inc., 6611 Tributary Street, Baltimore, MD 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: David
authors.initials: D
authors.lastname: Dain
authors.forename: Mark
authors.initials: M
authors.lastname: Ginski
authors.forename: Susan
authors.initials: S
authors.lastname: Lautar
authors.forename: Kathy
authors.initials: K
authors.lastname: Lee-Wisdom
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: Lisa
authors.initials: L
authors.lastname: Morgan
authors.forename: Bert
authors.initials: B
authors.lastname: Thomas
authors.forename: Lawrence R
authors.initials: LR
authors.lastname: Williams
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.forename: Yinong
authors.initials: Y
authors.lastname: Zhou
authors.forename: Vincent J
authors.initials: VJ
authors.lastname: Kalish
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry; D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use*; D001665:Binding Sites; D002545:Brain Ischemia / Q000188:drug therapy*; D018938:Caco-2 Cells; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use*; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D001569:Benzodiazepines