Discovery and SAR of 2-(1-propylpiperidin-4-yl)-1H-benzimidazole-4-carboxamide: A potent inhibitor of poly(ADP-ribose) polymerase (PARP) for the treatment of cancer.
We have developed a series of cyclic amine-containing benzimidazole carboxamide poly(ADP-ribose)polymerase (PARP) inhibitors, with good PARP-1 enzyme potency, as well as cellular potency. These efforts led to the identification of a lead preclinical candidate, 10b, 2-(1-propylpiperidin-4-yl)-1H-benzimidazole-4-carboxamide (A-620223). 10b displayed very good potency against both the PARP-1 enzyme with a K(i) of 8nM and in a whole cell assay with an EC(50) of 3nM. 10b is aqueous soluble, orally bioavailable across multiple species, and demonstrated good in vivo efficacy in a B16F10 subcutaneous murine melanoma model in combination with temozolomide (TMZ) and in an MX-1 breast xenograph model in combination with cisplatin.
Penning
Thomas D
TD
Cancer Research, GPRD, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA. thomas.penning@abbott.com
Zhu
Gui-Dong
GD
Gandhi
Viraj B
VB
Gong
Jianchun
J
Thomas
Sheela
S
Lubisch
Wilfried
W
Grandel
Roland
R
Wernet
Wolfgang
W
Park
Chang H
CH
Fry
Elizabeth H
EH
Liu
Xuesong
X
Shi
Yan
Y
Klinghofer
Vered
V
Johnson
Eric F
EF
Donawho
Cherrie K
CK
Frost
David J
DJ
Bontcheva-Diaz
Velitchka
V
Bouska
Jennifer J
JJ
Olson
Amanda M
AM
Marsh
Kennan C
KC
Luo
Yan
Y
Rosenberg
Saul H
SH
Giranda
Vincent L
VL
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001562:Benzimidazoles / Q000737:chemistry* / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy*; D002945:Cisplatin / Q000627:therapeutic use; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008546:Melanoma, Experimental / Q000188:drug therapy*; D051379:Mice; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D013329:Structure-Activity Relationship; D000077204:Temozolomide; D014183:Transplantation, Heterologous; D023041:Xenograft Model Antitumor Assays
D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D003606:Dacarbazine; D002945:Cisplatin; D000077204:Temozolomide