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

被引：238

作者：

Penning, Thomas D. ^{[1
]}

Zhu, Gui-Dong ^{[1
]}

Gandhi, Viraj B. ^{[1
]}

Gong, Jianchun ^{[1
]}

Liu, Xuesong ^{[1
]}

Shi, Yan ^{[1
]}

Klinghofer, Vered ^{[1
]}

Johnson, Eric F. ^{[1
]}

Donawho, Cherrie K. ^{[1
]}

Frost, David J. ^{[1
]}

Bontcheva-Diaz, Velitchka ^{[1
]}

Bouska, Jennifer J. ^{[1
]}

Osterling, Donald J. ^{[1
]}

Olson, Amanda M. ^{[1
]}

Marsh, Kerman C. ^{[2
]}

Luo, Yan ^{[1
]}

Giranda, Vincent L. ^{[1
]}

机构：

[1] Abbott Labs, GPRD, Canc Res, Abbott Pk, IL 60064 USA

[2] Abbott Labs, GPRD, Pharmacokinet, Abbott Pk, IL 60064 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2009年 / 52卷 / 02期

关键词：

ADP-RIBOSE POLYMERASE; POTENT; HOMOLOGY; THERAPY; MODELS; AGENTS;

D O I：

10.1021/jm801171j

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 EC50 Of 2 nM. In addition, 3a is aqueous soluble, orally bioavailable across multiple species, and demonstrated good in vivo efficacy in a B 16F10 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.

引用

页码：514 / 523

页数：10

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