The management of blood glucose levels and the avoidance of diabetic hyperglycemia are common objectives of many therapies in the treatment of diabetes. An aryl piperazine compound 3a (RTC1) has been described as a promoter of glucose uptake, in part through a cellular mechanism that involves inhibition of NADH:ubiquinone oxidoreductase. We report herein the synthesis of 41 derivatives of 3a (RTC1) and a systematic structure-activity-relationship study where a number of compounds were shown to effectively stimulate glucose uptake in vitro and inhibit NADH:ubiquinone oxidoreductase. The hit compound 3a (RTC1) remained the most efficacious with a 2.57 fold increase in glucose uptake compared to vehicle control and micromolar inhibition of NADH:ubiquinone oxidoreductase (IC₅₀ = 27 μM). In vitro DMPK and in vivo PK studies are also described, where results suggest that 3a (RTC1) would not be expected to provoke adverse drug-drug interactions, yet be readily metabolised, avoid rapid excretion, with a short half-life, and have good tissue distribution. The overall results indicate that aryl piperazines, and 3a (RTC1) in particular, have potential as effective agents for the treatment of diabetes.

血糖水平的控制和避免糖尿病性高血糖是糖尿病治疗中许多疗法的共同目标。芳基哌嗪化合物3a（RTC1）已被描述为葡萄糖摄取的促进剂，部分是通过涉及抑制NADH：泛醌氧化还原酶的细胞机制。我们在此报告了3a（RTC1）的41种衍生物的合成和系统的结构-活性-关系研究，其中许多化合物被证明可以有效地刺激体外葡萄糖的摄取并抑制NADH：泛醌氧化还原酶。命中化合物3a（RTC1）仍然是最有效的，与媒介物对照和NADH：泛醌氧化还原酶（IC ₅₀  = 27μM）的微摩尔抑制相比，葡萄糖摄取增加了2.57倍。还描述了体外DMPK和体内PK研究，结果表明不会期望3a（RTC1）引起药物与药物的不良相互作用，但易于代谢，避免快速排泄，半衰期短并且具有良好的组织分布。总体结果表明，芳基哌嗪，尤其是3a（RTC1）作为治疗糖尿病的有效药物具有潜力。