Froriep Danilo, Clement Bernd, Bittner Florian, Mendel Ralf R, Reichmann Debora, Schmalix Wolfgang, Havemeyer Antje
Department of Pharmaceutical and Medicinal Chemistry, Pharmaceutical Institute, Christian-Albrechts-University of Kiel, Kiel, Germany.
Xenobiotica. 2013 Sep;43(9):780-4. doi: 10.3109/00498254.2013.767481. Epub 2013 Feb 4.
Upamostat (Mesupron®) is a new small molecule serine protease inhibitor. The drug candidate was developed to inhibit the urokinase-type plasminogen activator (uPA) system, which plays a major role in tumor invasion and metastasis. Upamostat is currently in clinical development as an anti-metastatic and non-cytotoxic agent against pancreatic and breast cancer. Upamostat is the orally available amidoxime- (i.e. hydroxyamidine-) prodrug of the pharmacologically active form, WX-UK1. In this study, the reductive enzymatic activation of upamostat to its corresponding amidine WX-UK1 was analyzed. The recently discovered molybdenum enzyme "mitochondrial Amidoxime Reducing Component" (mARC) catalyses together with its electron transport proteins cytochrome b₅ and NADH cytochrome b₅ reductase the reduction of N-hydroxylated prodrugs. In vitro biotransformation assays with porcine subcellular fractions and the reconstituted human enzymes demonstrate an mARC-dependent N-reduction of upamostat.
乌帕司他（Mesupron®）是一种新型小分子丝氨酸蛋白酶抑制剂。该候选药物旨在抑制尿激酶型纤溶酶原激活剂（uPA）系统，该系统在肿瘤侵袭和转移中起主要作用。乌帕司他目前正处于临床开发阶段，作为一种抗转移且无细胞毒性的药物用于治疗胰腺癌和乳腺癌。乌帕司他是具有药理活性形式WX-UK1的口服可用偕胺肟（即羟脒）前药。在本研究中，分析了乌帕司他向其相应脒WX-UK1的还原酶促激活过程。最近发现的钼酶“线粒体偕胺肟还原成分”（mARC）与其电子转运蛋白细胞色素b₅和NADH细胞色素b₅还原酶一起催化N-羟基化前药的还原反应。用猪亚细胞组分和重组人酶进行的体外生物转化试验表明，乌帕司他的N-还原反应依赖于mARC。
