Discovery and SAR of 2-(1-propylpiperidin-4-yl)-1H

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• 作者：Thomas D. Penning ; Gui-Dong Zhu ; Viraj B. G ; hi ; Jianchun Gong ; Sheela Thomas ; Wilfried Lubisch ; Rol ; Gr ; el ; Wolfgang Wernet ; Chang H. Park ; Elizabeth H. Fry ; Xuesong Liu ; Yan Shi ; Vered Klinghofer ; Er
• 关键词：Poly(ADP-ribose)polymerase ; PARP inhibitor ; A-620223 ; Benzimidazole carboxamide
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2008
• 出版时间：15 July 2008
• 年：2008
• 卷：16
• 期：14
• 页码：6965-6975
• 全文大小：384 K

文摘

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 8 nM and in a whole cell assay with an EC₅₀ 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.