Synthesis and SAR of novel, potent and orally bioavailable benzimidazole inhibitors of poly(ADP-ribose) polymerase (PARP) with a quaternary methylene-amino substituent.
Poly(ADP-ribose) polymerases (PARPs) play significant roles in various cellular functions including DNA repair and control of RNA transcription. PARP inhibitors have been demonstrated to potentiate the effect of cytotoxic agents or radiation in a number of animal tumor models. Utilizing a benzimidazole carboxamide scaffold in which the amide forms a key intramolecular hydrogen bond for optimal interaction with the enzyme, we have identified a novel series of PARP inhibitors containing a quaternary methylene-amino substituent at the C-2 position of the benzimidazole. Geminal dimethyl analogs at the methylene-amino substituent were typically more potent than mono-methyl derivatives in both intrinsic and cellular assays. Smaller cycloalkanes such as cyclopropyl or cyclobutyl were tolerated at the quaternary carbon while larger rings were detrimental to potency. In vivo efficacy data in a B16F10 murine flank melanoma model in combination with temozolomide (TMZ) are described for two optimized analogs.
Zhu
Gui-Dong
GD
Cancer Research, GPRD, Abbott Laboratories, Abbott Park, IL 60064, USA. Gui-Dong.Zhu@abbott.com
Gandhi
Viraj B
VB
Gong
Jianchun
J
Thomas
Sheela
S
Luo
Yan
Y
Liu
Xuesong
X
Shi
Yan
Y
Klinghofer
Vered
V
Johnson
Eric F
EF
Frost
David
D
Donawho
Cherrie
C
Jarvis
Ken
K
Bouska
Jennifer
J
Marsh
Kennan C
KC
Rosenberg
Saul H
SH
Giranda
Vincent L
VL
Penning
Thomas D
TD
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical / Q000295:instrumentation* / Q000379:methods; D004247:DNA / Q000737:chemistry; D004260:DNA Repair; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D007700:Kinetics; D051379:Mice; D009368:Neoplasm Transplantation; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D014158:Transcription, Genetic
D000970:Antineoplastic Agents; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D004247:DNA