School of Pharmacy, Wenzhou Medical College, 1# Jingguan Road, College Town, Wenzhou City 325035, China.
Curr Med Chem. 2010;17(5):412-22. doi: 10.2174/092986710790226147.
Glucocorticoids (GC) play a fundamental role in controlling physiologic homeostasis and, when present in excess, can have a detrimental impact on glucose control, blood pressure and lipid levels. The oxidoreductase 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) mainly catalyzes the intracellular regeneration of active GCs (cortisol, corticosterone) from inert inactive 11-keto forms (cortisone) in liver, adipose tissue and brain, amplifying local GC action. Multiple lines of evidence have indicated that 11beta-HSD1-mediated intracellular cortisol production may have a pathogenic role in type 2 diabetes and its co-morbidities. The 11beta-HSD1 becomes a novel target for anti-type 2 diabetes drug developments, and inhibition of 11beta-HSD1 offers a potential therapy to attenuate the type 2 diabetes. In the past several years, a lot of 11beta-HSD1 inhibitors have been designed, synthesized, screened and discovered. Lowering intracellular glucocorticoid concentrations through administration of small molecule 11beta-HSD1 selective inhibitors, significantly attenuates the signs and symptoms of disease in preclinical animal models and clinical trials of diabetes and metabolic syndrome. Among published inhibitors, DIO-902 from DiObex Inc. and INCB13739 from Incyte Inc. are now being investigated under Phase 2B clinical trials. However, the selectivity of current selective 11beta-HSD1 inhibitors has been just focused on the difference between 11beta-HSD1 and 11beta-HSD2. They inhibit the bi-directional activities of 11beta-HSD1, both 11beta-HSD1 reductase (major) and oxidase (minor). In our lab, we have recently found novel chemicals that not only inhibit 11beta-HSD1 reductase activity but also increase its oxidase activity without inhibition against 11beta-HSD2. We propose that this dual modulation on 11beta-HSD1 may provide a better therapeutic strategy for type 2 diabetes.
糖皮质激素（GC）在控制生理稳态方面起着至关重要的作用，而当 GC 过量存在时，会对葡萄糖控制、血压和血脂水平产生不利影响。氧化还原酶 11β-羟类固醇脱氢酶 1 型（11β-HSD1）主要催化肝脏、脂肪组织和大脑中活性 GC（皮质醇、皮质酮）从无活性的 11-酮形式（可的松）的细胞内再生，从而放大局部 GC 作用。多条证据表明，11β-HSD1 介导的细胞内皮质醇产生可能在 2 型糖尿病及其合并症中具有致病作用。11β-HSD1 成为抗 2 型糖尿病药物开发的新靶点，抑制 11β-HSD1 提供了一种潜在的治疗方法来减轻 2 型糖尿病。在过去的几年中，已经设计、合成、筛选和发现了大量的 11β-HSD1 抑制剂。通过给予小分子 11β-HSD1 选择性抑制剂来降低细胞内糖皮质激素浓度，可显著减轻临床前动物模型和糖尿病及代谢综合征临床试验中的疾病症状和体征。在已发表的抑制剂中，DiObex Inc. 的 DIO-902 和 Incyte Inc. 的 INCB13739 目前正在进行 2B 期临床试验。然而，目前选择性 11β-HSD1 抑制剂的选择性仅集中在 11β-HSD1 和 11β-HSD2 之间的差异上。它们抑制 11β-HSD1 的双向活性，即 11β-HSD1 还原酶（主要）和氧化酶（次要）。在我们的实验室中，我们最近发现了不仅抑制 11β-HSD1 还原酶活性，而且还增加其氧化酶活性而不抑制 11β-HSD2 的新型化学物质。我们提出，这种对 11β-HSD1 的双重调节可能为 2 型糖尿病提供更好的治疗策略。
