We have developed a series of phenylpyrrolidine- and phenylpiperidine-substituted benzimidazole carboxamide poly(ADP-ribose) polymerase (PARP) inhibitors with excellent PARP enzyme potency as well as single-digit nanomolar cellular potency. These efforts led to the identification of (S)-2-(2-fluoro-4-(pyrrolidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide (22b, A-966492). Compound 22b displayed excellent potency against the PARP-1 enzyme with a K_i of 1 nM and an EC₅₀ of 1 nM in a whole cell assay. In addition, 22b is orally bioavailable across multiple species, crosses the blood−brain barrier, and appears to distribute into tumor tissue. It also demonstrated good in vivo efficacy in a B16F10 subcutaneous murine melanoma model in combination with temozolomide and in an MX-1 breast cancer xenograft model both as a single agent and in combination with carboplatin.

中文翻译：

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苯基取代的苯并咪唑羧酰胺聚（ADP-核糖）聚合酶抑制剂的优化：（S）-2-（2-氟-4-（吡咯烷-2-基）苯基）-1 H-苯并咪唑-4-羧酰胺的鉴定（ A-966492），一种高效有效的抑制剂

我们已经开发了一系列的苯基吡咯烷和苯基哌啶取代的苯并咪唑羧酰胺聚（ADP-核糖）聚合酶（PARP）抑制剂，具有优异的PARP酶效能以及个位数纳摩尔细胞效能。这些努力导致鉴定了（S）-2-（2-氟-4-（吡咯烷基-2-基）苯基）-1 H-苯并咪唑-4-羧酰胺（22b，A-966492）。化合物22B显示针对PARP-1酶优异效力与ķ_我为1nM和EC ₅₀在全细胞测定中为1nM。另外22b可跨多种物种口服生物利用，穿过血脑屏障，并似乎分布在肿瘤组织中。它在与替莫唑胺联用的B16F10皮下鼠黑色素瘤模型中以及在作为单药和与卡铂联用的MX-1乳腺癌异种移植模型中均显示出良好的体内疗效。