Glucokinase (GK) is a key regulator of glucose homeostasis, and its small-molecule activators represent a promising opportunity for the treatment of type 2 diabetes. Several GK activators have been advanced into clinical trials and have demonstrated promising efficacy; however, hypoglycemia represents a key risk for this mechanism. In an effort to mitigate this hypoglycemia risk while maintaining the efficacy of the GK mechanism, we have investigated a series of amino heteroaryl phosphonate benzamides as ‘‘partial” GK activators. The structure–activity relationship studies starting from a “full GK activator” 11, which culminated in the discovery of the “partial GK activator” 31 (BMS-820132), are discussed. The synthesis and in vitro and in vivo preclinical pharmacology profiles of 31 and its pharmacokinetics (PK) are described. Based on its promising in vivo efficacy and preclinical ADME and safety profiles, 31 was advanced into human clinical trials.

中文翻译：

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发现部分葡萄糖激酶激活剂临床候选物：二乙基（(3-(3-((5-(Azetidine-1-carbonyl)pyrazin-2-yl)oxy)-5-isopropoxybenzamido)-1H-pyrazol-1-yl)甲基）膦酸酯（BMS-820132）

葡萄糖激酶 (GK) 是葡萄糖稳态的关键调节剂，其小分子激活剂代表了治疗 2 型糖尿病的有希望的机会。几种 GK 激活剂已进入临床试验并显示出有希望的疗效；然而，低血糖是这种机制的主要风险。为了减轻这种低血糖风险，同时保持 GK 机制的功效，我们研究了一系列氨基杂芳基膦酸酯苯甲酰胺作为“部分”GK 激活剂。讨论了从“全 GK 激活剂” 11开始的结构-活性关系研究，最终发现了“部分 GK 激活剂” 31 (BMS-820132)。合成和体外和体内描述了31的临床前药理学概况及其药代动力学 (PK)。基于其有希望的体内疗效和临床前 ADME 和安全性，31已进入人体临床试验。