title: Discovery and SAR of orally efficacious tetrahydropyridopyridazinone PARP inhibitors for the treatment of cancer.
abstract: PARP-1, the most abundant member of the PARP superfamily of nuclear enzymes, has emerged as a promising molecular target in the past decade particularly for the treatment of cancer. A number of PARP-1 inhibitors, including veliparab discovered at Abbott, have advanced into different stages of clinical trials. Herein we describe the development of a new tetrahydropyridopyridazinone series of PARP-1 inhibitors. Many compounds in this class, such as 20w, displayed excellent potency against the PARP-1 enzyme with a K(i) value of <1nM and an EC(50) value of 1nM in a C41 whole cell assay. The presence of the NH in the tetrahydropyridyl ring of the tetrahydropyridopyridazinone scaffold improved the pharmacokinetic properties over similar carbon based analogs. Compounds 8c and 20u are orally available, and have demonstrated significant efficacy in a B16 murine xenograft model, potentiating the efficacy of temozolomide (TMZ).
authors: Cancer Research, GPRD, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA. gui-dong.zhu@abbott.com
authors: Gui-Dong
authors: GD
authors: Zhu
authors: Jianchun
authors: J
authors: Gong
authors: Viraj B
authors: VB
authors: Gandhi
authors: Xuesong
authors: X
authors: Liu
authors: Yan
authors: Y
authors: Shi
authors: Eric F
authors: EF
authors: Johnson
authors: Cherrie K
authors: CK
authors: Donawho
authors: Paul A
authors: PA
authors: Ellis
authors: Jennifer J
authors: JJ
authors: Bouska
authors: Donald J
authors: DJ
authors: Osterling
authors: Amanda M
authors: AM
authors: Olson
authors: Chang
authors: C
authors: Park
authors: Yan
authors: Y
authors: Luo
authors: Alexander
authors: A
authors: Shoemaker
authors: Vincent L
authors: VL
authors: Giranda
authors: Thomas D
authors: TD
authors: Penning
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000201:enzymology; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011724:Pyridazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011724:Pyridazines; D011725:Pyridines; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases