title: Discovery of potent poly(ADP-ribose) polymerase-1 inhibitors from the modification of indeno[1,2-c]isoquinolinone.
abstract: Novel indeno[1,2-c]isoquinolinone derivatives were synthesized and evaluated as inhibitors of the nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1). These potent nonmutagenic PARP-1 inhibitors possess an additional five-membered ring between the B and C rings of 6(5H)-phenanthridinone. The most potent PARP-1 inhibitors were obtained from the substitution of the D ring at the C-9 position, in particular sulfonamide and N-acyl analogues (6 and 11). The 9-sulfonamide analogues 11a and 12a exhibited IC(50) values of 1 and 10 nM, respectively.
authors.affiliation: Inotek Pharmaceuticals Corporation, 100 Cummings Center, Suite 419E, Beverly, MA 01915, USA. pjagtap@inotekcorp.com
authors.forename: Prakash G
authors.initials: PG
authors.lastname: Jagtap
authors.forename: Erkan
authors.initials: E
authors.lastname: Baloglu
authors.forename: Garry J
authors.initials: GJ
authors.lastname: Southan
authors.forename: Jon G
authors.initials: JG
authors.lastname: Mabley
authors.forename: Hongshan
authors.initials: H
authors.lastname: Li
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
authors.forename: John
authors.initials: J
authors.lastname: van Duzer
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Salzman
authors.forename: Csaba
authors.initials: C
authors.lastname: Szabó
mesh_terms: D007192:Indenes / Q000138:chemical synthesis* / Q000737:chemistry; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D007192:Indenes; D007546:Isoquinolines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases