Synthesis and evaluation of a new generation of orally efficacious benzimidazole-based poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors as anticancer agents.
Small molecule inhibitors of PARP-1 have been pursued by various organizations as potential therapeutic agents either capable of sensitizing cytotoxic treatments or acting as stand-alone agents to combat cancer. As one of the strategies to expand our portfolio of PARP-1 inhibitors, we pursued unsaturated heterocycles to replace the saturated cyclic amine derivatives appended to the benzimidazole core. Not only did a variety of these new generation compounds maintain high enzymatic potency, many of them also displayed robust cellular activity. For example, the enzymatic IC(50) and cellular EC(50) values were as low as 1 nM or below. Compounds 24 (EC(50) = 3.7 nM) and 44 (EC(50) = 7.8 nM), featuring an oxadiazole and a pyridine moiety, respectively, demonstrated balanced potency and PK profiles. In addition, these two molecules exhibited potent oral in vivo efficacy in potentiating the cytotoxic agent temozolomide in a B16F10 murine melanoma model.
Tong
Yunsong
Y
Cancer Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064, USA. yunsong.tong@abbott.com
Bouska
Jennifer J
JJ
Ellis
Paul A
PA
Johnson
Eric F
EF
Leverson
Joel
J
Liu
Xuesong
X
Marcotte
Patrick A
PA
Olson
Amanda M
AM
Osterling
Donald J
DJ
Przytulinska
Magdalena
M
Rodriguez
Luis E
LE
Shi
Yan
Y
Soni
Nirupama
N
Stavropoulos
Jason
J
Thomas
Sheela
S
Donawho
Cherrie K
CK
Frost
David J
DJ
Luo
Yan
Y
Giranda
Vincent L
VL
Penning
Thomas D
TD
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D018906:Antineoplastic Agents, Alkylating; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D004357:Drug Synergism; D005260:Female; D006801:Humans; D008297:Male; D008546:Melanoma, Experimental / Q000188:drug therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D010069:Oxadiazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011725:Pyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship; D000077204:Temozolomide; D014183:Transplantation, Heterologous
C545544:2-(4-(1,3,4-oxadiazol-2-yl)phenyl)-1H-benzo(d)imidazole-4-carboxamide; C545545:2-(4-(pyridin-2-yl)phenyl)-1H-benzo(d)imidazole-4-carboxamide; D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D001562:Benzimidazoles; D010069:Oxadiazoles; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011725:Pyridines; D003606:Dacarbazine; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D000077204:Temozolomide