Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713GZ Groningen, Netherlands; Sulfateq B.V., Admiraal de Ruyterlaan 5, 9726GN, Groningen, Netherlands; Cardiovascular Regenerative Medicine, Dept. Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713GZ Groningen, Netherlands.
Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713GZ Groningen, Netherlands; Department of Pharmacology & Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Odbojárov 10, 832 32, Bratislava, Slovakia.
Eur J Pharm Sci. 2022 Jan 1;168:106033. doi: 10.1016/j.ejps.2021.106033. Epub 2021 Oct 3.
Acute kidney injury (AKI) is a global healthcare burden attributable to high mortality and staggering costs of dialysis. The underlying causes of AKI include hypothermia and rewarming (H/R), ischemia/reperfusion (I/R), mitochondrial dysfunction and reactive oxygen species production. Inspired by the mechanisms conferring organ protection in hibernating hamster, 6-chromanol derived compounds were developed to address the need of effective prevention and treatment of AKI. Here we report on the pre-clinical screening of 6-chromanol leads that confer protection during I/R to select compounds with favorable profiles for clinical testing in AKI. A library of 6-chromanols (n = 63) was screened in silico for pharmacochemical properties and druggability. Selected compounds (n = 15) were screened for the potency to protect HEK293 cells from H/R cell death and subjected to a panel of in vitro safety assays. Based on these parameters, SUL-138 was selected as the lead compound and was found to safeguard kidney function and decrease renal injury after I/R in rats. The compound was without cardiovascular or respiratory effects in vivo. SUL-138 pharmacokinetics of control animals (mouse, rat) and those undergoing I/R (rat) was identical, showing a two-phase elimination profile with terminal half-life of about 8 h. Collectively, our phenotype-based screening approach led to the identification of 3 candidates for pre-clinical studies (5%, 3/64). SUL-138 emerged from this small-scale library of 6-chromanols as a novel prophylactic for AKI. The presented efficacy and safety data provide a basis for future development and clinical testing. SECTION ASSIGNMENTS: : Drug discovery and translational medicine, renal, metabolism SIGNIFICANCE STATEMENT: : Based on in silico druggability parameters, a 63 compound 6-chromanol library was narrowed down to 15 compounds. These compounds were subjected to phenotypical screening of cell survival following hypothermia damage and hit compounds were identified. After subsequent assessment of in vivo efficacy, toxicity, pharmacokinetics, and cardiovascular and respiratory safety, SUL-138 emerged as a lead compound that prevented kidney injury after ischemia/reperfusion and demonstrated a favorable pharmacokinetic profile unaffected by renal ischemia.
急性肾损伤 (AKI) 是一种全球性的医疗保健负担，其死亡率高，透析费用高昂。AKI 的根本原因包括低温和复温（H/R）、缺血/再灌注 (I/R)、线粒体功能障碍和活性氧的产生。受冬眠仓鼠中赋予器官保护机制的启发，开发了 6-色满醇衍生化合物，以满足有效预防和治疗 AKI 的需求。在这里，我们报告了 6-色满醇先导化合物的临床前筛选结果，这些化合物在 I/R 期间具有保护作用，以选择具有 AKI 临床测试良好特征的化合物。对 6-色满醇库 (n=63) 进行了计算机筛选，以评估其药物化学性质和可药性。选择了一些具有潜力的化合物 (n=15)，用于筛选其保护 HEK293 细胞免受 H/R 细胞死亡的能力，并进行了一系列体外安全检测。基于这些参数，选择 SUL-138 作为先导化合物，发现它可以保护肾脏功能，并在大鼠 I/R 后降低肾损伤。该化合物在体内对心血管和呼吸系统没有影响。对照动物（小鼠、大鼠）和经历 I/R（大鼠）的 SUL-138 的药代动力学相同，具有约 8 小时的两相消除特征。总的来说，我们基于表型的筛选方法导致了 3 种候选药物进入临床前研究（5%，3/64）。SUL-138 是从这个 6-色满醇的小库中筛选出来的一种新型 AKI 预防药物。所呈现的疗效和安全性数据为进一步的开发和临床测试提供了基础。 部分分配：药物发现和转化医学，肾脏，代谢 意义声明：基于可药性参数的计算机筛选，将 63 种 6-色满醇化合物缩小到 15 种化合物。对这些化合物进行了低温损伤后细胞存活的表型筛选，并鉴定出了命中化合物。随后评估了体内疗效、毒性、药代动力学以及心血管和呼吸安全性，SUL-138 成为一种预防缺血/再灌注后肾损伤的先导化合物，具有良好的药代动力学特征，不受肾缺血的影响。
