Discovery and SAR of orally efficacious tetrahydropyridopyridazinone PARP inhibitors for the treatment of cancer

Gui-Dong Zhu; Jianchun Gong; Viraj B Gandhi; Xuesong Liu; Yan Shi; Eric F Johnson; Cherrie K Donawho; Paul A Ellis; Jennifer J Bouska; Donald J Osterling; Amanda M Olson; Chang Park; Yan Luo; Alexander Shoemaker; Vincent L Giranda; Thomas D Penning

doi:10.1016/j.bmc.2012.06.021

Discovery and SAR of orally efficacious tetrahydropyridopyridazinone PARP inhibitors for the treatment of cancer

Bioorg Med Chem. 2012 Aug 1;20(15):4635-45. doi: 10.1016/j.bmc.2012.06.021. Epub 2012 Jun 19.

Authors

Gui-Dong Zhu¹, Jianchun Gong, Viraj B Gandhi, Xuesong Liu, Yan Shi, Eric F Johnson, Cherrie K Donawho, Paul A Ellis, Jennifer J Bouska, Donald J Osterling, Amanda M Olson, Chang Park, Yan Luo, Alexander Shoemaker, Vincent L Giranda, Thomas D Penning

Affiliation

¹ Cancer Research, GPRD, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA. gui-dong.zhu@abbott.com

PMID: 22766219
DOI: 10.1016/j.bmc.2012.06.021

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).

MeSH terms

Administration, Oral
Animals
Antineoplastic Agents / administration & dosage
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / pharmacology*
Crystallography, X-Ray
Dose-Response Relationship, Drug
Drug Discovery*
Enzyme Inhibitors / administration & dosage
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / pharmacology*
Female
Mice
Mice, Inbred C57BL
Models, Molecular
Molecular Structure
Neoplasms, Experimental / drug therapy*
Neoplasms, Experimental / enzymology
Poly (ADP-Ribose) Polymerase-1
Poly(ADP-ribose) Polymerase Inhibitors*
Poly(ADP-ribose) Polymerases / metabolism
Pyridazines / chemical synthesis
Pyridazines / chemistry
Pyridazines / pharmacology*
Pyridines / chemical synthesis
Pyridines / chemistry
Pyridines / pharmacology*
Structure-Activity Relationship
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents
Enzyme Inhibitors
Poly(ADP-ribose) Polymerase Inhibitors
Pyridazines
Pyridines
Parp1 protein, mouse
Poly (ADP-Ribose) Polymerase-1
Poly(ADP-ribose) Polymerases