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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

jgsun 添加于 2010-10-10 23:46 | 1988 次阅读 | 0 个评论

作者
Penning TD, Zhu G-D, Gandhi VB, Gong J, Thomas S, Lubisch W, Grandel R, Wernet W, Park CH, Fry EH
摘要
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)-1 H -benzimidazole-4-carboxamide (A-620223). 10b displayed very good potency against both the PARP -1 enzyme with a K i of 8 nM and in a whole cell assay with an EC 50 of 3 nM. 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.
详细资料
- 文献种类: Journal Article
- 期刊名称: Bioorganic & Medicinal Chemistry
- 期刊缩写: Bioorganic & Medicinal Chemistry
- 期卷页: 2008年第16卷第14期 6965-6975页
- ISBN: 0968-0896
学科领域生物医药 » 药学
标签

Parp inhibitor
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