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
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
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DOI：
10.1021/jm801171j
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发表时间：
2009-01-22
影响因子：
7.3
通讯作者：
Giranda, Vincent L.
中科院分区：
文献类型：
--
作者：
Penning, Thomas D.;Zhu, Gui-Dong;Giranda, Vincent L.
我们开发了一系列含环胺的苯并咪唑甲酰胺PARP抑制剂，在苯并咪唑环系统的连接点处具有甲基取代的季铵中心。这些化合物表现出优异的PARP酶效力以及个位数纳摩尔细胞效力。这些努力导致了3a（2-[（R）-2-甲基吡咯烷-2-基]-1H-苯并咪唑-4-甲酰胺，ABT-888）的鉴定，目前在人体I期临床试验中。化合物3a显示出针对PARP-1和PARP-2酶的优异效力，Ki为5 nM，并且在C41全细胞测定中EC 50为2nM。此外，3a是水溶性的，在多个物种中可口服生物利用，并且在与替莫唑胺（TMZ）组合的B 16 F10皮下鼠黑素瘤模型中和在与卡铂或环磷酰胺组合的MX-1乳腺癌异种移植物模型中显示出良好的体内功效。
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.