The need for improved medications for the treatment of epilepsy and chronic pain is essential. Epileptic patients typically take multiple antiseizure drugs without complete seizure freedom, and chronic pain is not fully managed with current medications. A positive allosteric modulator (PAM) of α2/3-containing GABA_A receptors (5-(8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f]imidazole[1,5-α][1,4]diazepin-3-yl) oxazole or KRM-II-81 (8) is a lead compound in a series of imidazodiazepines. We previously reported that KRM-II-81 produces broad-based anticonvulsant and antinociceptive efficacy in rodent models and provides a wider margin over motoric side effects than that of other GABA_A receptor PAMs. The present series of experiments was designed to fill key missing gaps in prior preclinical studies assessing whether KRM-II-81 could be further differentiated from nonselective GABA_A receptor PAMs using the anticonvulsant diazepam (DZP) as a comparator. In multiple chemical seizure provocation models in mice, KRM-II-81 was either equally or more efficacious than DZP. Most strikingly, KRM-II-81 but not DZP blocked the development of seizure sensitivity to the chemoconvulsants cocaine and pentylenetetrazol in seizure kindling models. These and predecessor data have placed KRM-II-81 into consideration for clinical development requiring the manufacture of kilogram amounts of good manufacturing practice material. We describe here a novel synthetic route amenable to kilogram quantity production. The new biological and chemical data provide key steps forward in the development of KRM-II-81 (8) as an improved treatment option for patients suffering from epilepsy.

中文翻译：

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咪唑二氮杂类抗惊厥药KRM-II-81可产生新型的非地西p样抗癫痫发作作用。

需要用于治疗癫痫和慢性疼痛的改良药物是必不可少的。癫痫患者通常在没有完全癫痫发作自由的情况下服用多种抗癫痫药，并且当前的药物不能完全控制慢性疼痛。含α2/ 3的GABA _A受体的正构构调节剂（PAM）（5-（8-乙炔基-6-（吡啶-2-基）-4 H-苯并[ f ]咪唑[1,5-α] [ 1,4] diazepin-3-yl）oxazole或KRM-II-81（8）是一系列咪唑二氮杂类中的先导化合物，我们先前曾报道KRM-II-81在啮齿动物模型中具有广泛的抗惊厥和镇痛作用与其他GABA _A相比，它在运动副作用方面的裕度更大受体PAM。本系列实验旨在填补先前的临床前研究中的关键缺失缺口，以评估KRM-II-81是否可以与非选择性GABA _A进一步区分使用抗惊厥性地西epa（DZP）作为比较剂的受体PAM。在小鼠的多种化学性癫痫激发模型中，KRM-II-81与DZP具有同等效力或更有效。最惊人的是，在癫痫发作模型中，KRM-II-81而非DZP阻止了癫痫发作对化学惊厥剂可卡因和戊四氮的敏感性的发展。这些和之前的数据已将KRM-II-81纳入需要开发千克量的良好生产规范材料的临床开发中。我们在这里描述了一种适合公斤数量生产的新颖合成路线。新的生物学和化学数据为开发KRM-II-81（8）提供了重要的步骤，KRM-II-81（8）作为癫痫患者的一种改进的治疗选择。