Discovery of the Poly(ADP-ribose) polymerase (PARP) inhibitor 2-[(R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide (ABT-888) for the treatment of cancer.
We have developed a series of cyclic amine-containing benzimidazole carboxamide PARP inhibitors with a methyl-substituted quaternary center at the point of attachment to the benzimidazole ring system. These compounds exhibit excellent PARP enzyme potency as well as single-digit nanomolar cellular potency. These efforts led to the identification of 3a (2-[(R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide, ABT-888), currently in human phase I clinical trials. Compound 3a displayed excellent potency against both the PARP-1 and PARP-2 enzymes with a K(i) of 5 nM and in a C41 whole cell assay with an EC(50) of 2 nM. In addition, 3a 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 cancer xenograft model in combination with either carboplatin or cyclophosphamide.
Penning
Thomas D
TD
Cancer Research, Pharmacokinetics, GPRD, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064, USA. thomas.penning@abbott.com
Zhu
Gui-Dong
GD
Gandhi
Viraj B
VB
Gong
Jianchun
J
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
Osterling
Donald J
DJ
Olson
Amanda M
AM
Marsh
Kennan C
KC
Luo
Yan
Y
Giranda
Vincent L
VL
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D001562:Benzimidazoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D016190:Carboplatin / Q000008:administration & dosage; D003520:Cyclophosphamide / Q000008:administration & dosage; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004285:Dogs; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D000882:Haplorhini; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008546:Melanoma, Experimental / Q000473:pathology*; D051379:Mice; D016513:Mice, SCID; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051381:Rats; D000077204:Temozolomide
D000970:Antineoplastic Agents; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C521013:veliparib; D003606:Dacarbazine; D003520:Cyclophosphamide; D016190:Carboplatin; D000077204:Temozolomide