Eisenmann Michael, Steuber Holger, Zentgraf Matthias, Altenkämper Mirko, Ortmann Regina, Perruchon Johann, Klebe Gerhard, Schlitzer Martin
Institut für Pharmazeutische Chemie, Philipps Universität Marburg, Marbacher Weg 6, 35032 Marburg, Germany.
ChemMedChem. 2009 May;4(5):809-19. doi: 10.1002/cmdc.200800410.
Diabetes mellitus is a universal health problem. The World Health Organization (WHO) estimates that 150 million people suffer from diabetes mellitus worldwide in 2005. Long-term complications are a serious problem in the treatment of diabetes, manifesting in macrovascular and microvascular complications. Sorbitol accumulation has been proposed to be an important factor in the development of microvascular complications such as nephropathy, neuropathy, retinopathy or cataract. Catalyzing the NADPH-dependent reduction of glucose to sorbitol, aldose reductase (ALR2) is an important target in the prevention of these complications. The development of novel aldose reductase inhibitors is expected to benefit strongly from a structure-based design approach. A virtual screening based on the ultrahigh-resolution crystal structure of the inhibitor IDD 594 in complex with human ALR2 identified two compounds with IC(50) values in the low micro- to submicromolar range. Based on the known interactions between the ligands and their binding pocket, we simplified the lead structures to give the minimal structural requirements and developed synthetic pathways from commercially available compounds. The newly synthesized compounds were assayed for their inhibition of ALR2, showing inhibitory activities down to the nanomolar range. Crystal structure analysis of the most potent derivative of our series revealed insights into the binding mode of the inhibitors.
糖尿病是一个全球性的健康问题。世界卫生组织（WHO）估计，2005年全球有1.5亿人患有糖尿病。长期并发症是糖尿病治疗中的一个严重问题，表现为大血管和微血管并发症。山梨醇积累被认为是肾病、神经病变、视网膜病变或白内障等微血管并发症发生发展的一个重要因素。醛糖还原酶（ALR2）催化NADPH依赖的葡萄糖还原为山梨醇，是预防这些并发症的一个重要靶点。新型醛糖还原酶抑制剂的开发有望从基于结构的设计方法中受益匪浅。基于抑制剂IDD 594与人ALR2复合物的超高分辨率晶体结构进行虚拟筛选，鉴定出两种IC(50)值在低微摩尔至亚微摩尔范围内的化合物。基于配体与其结合口袋之间的已知相互作用，我们简化了先导结构以给出最小结构要求，并从市售化合物开发了合成途径。对新合成的化合物进行了ALR2抑制活性测定，结果显示其抑制活性低至纳摩尔范围。对我们系列中最有效的衍生物进行晶体结构分析，揭示了抑制剂的结合模式。
