CHEMISTRY AND BIOLOGY OF INSULIN-LIKE VANADIUM COMPOUNDS

类胰岛素钒化合物的化学和生物学

• 批准号: 6519306
• 负责人: DEBBIE Catharina CRANS
• 金额: $ 33.82万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-04-01 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6519306
• 关键词: chemical registry /resource; chemical structure function; chemical synthesis; combinatorial chemistry; electron spin resonance spectroscopy; hypoglycemic agents; insulin receptor; laboratory rabbit; laboratory rat; metal complex; pharmacokinetics; phosphatase inhibitor; protein protein interaction; tissue /cell culture; vanadium

The insulin-line activity of vanadium compounds is currently of great interest given the recent Phase 1 clinical trial using oral organic vanadium (IV) (KP-102) treatment of diabetes. The organic vanadium compounds are superior to the simple vanadium salts (vanadate and vanadyl sulfate) with respect to their insulin-like effects and lower toxicity. This proposal has two goals. One goal is to characterize the mode of action of two different classes of organic vanadium compounds. The second goal is to identify new vanadium compounds with superior insulin-like activities and lower toxicity. The conventional wisdom on how vanadium compounds produce their insulin-enhancing effects is through inhibition of a tyrosine protein phosphatase acting on the insulin receptor and/or at points distal to the receptor in the insulin signaling pathway. Since no correlation has been reported for compound efficacy in animals and inhibition of a protein phosphatase, and recognizing the amounts of data available, it is appropriate at this time to entertain the hypothesis that no one target is sufficient to describe the mode of action of vanadium compounds. The multi-factor approach proposed here is developed on the premise that protein phosphatase inhibition and some other as yet unidentified parameter(s) combined are responsible for the mode of vanadium compounds. A systematic multi-factor mechanistic analysis of compound effects requires that effects are organized in categories (insulin-like, toxicity, pharmacology, cellular environment and chemical properties) each containing several parameters in a framework of compound profiles. The design of new compounds (Aim 1) will be used as a tool to test mechanistic hypotheses that will be developed based on data obtained in 11 assays (Aim 2). In addition, libraries of compounds prepared by combinatorial synthesis will be screened using 4 in vitro and cellular assays to identify superior compounds (Aim 2). Iterative evaluation of the performance of each compound/combinatorial library will lead to identification of key structural units. Finally, the compound profiles will guide selection of four compounds for detailed pharmacokinetic and distribution analysis (Aim 3). The Specific Aims we propose are: Aim 1. Preparation of Individual Vanadium Compounds and Combinatorial Libraries of Vanadium Compounds. The aqueous hydrolytic and redox chemistry of biologically active compounds will be characterized. Aim 2. Assays to Evaluate the Effects of Vanadium Compounds in Biological Systems In Vitro (Part A, phosphatase inhibition, protein interaction, lipophilicity and effects of cellular reducing agents), In Cell Culture (Part B, cell growth and viability, speciation of vanadium compounds in cells, stimulation by insulin receptor phosphorylation in normal and vanadium compound treated cells) and In Vanadium Treated Normal and STZ- Induced Diabetic Rats (Part C, efficacy for lowered elevated plasma glucose levels, insulin sensitivity, absorption of total vanadium into serum at steady state and phosphorylation of insulin receptor phosphorylation). Aim 3. Pharmacokinetic and Distribution Profiles of Organic Vanadium Compounds. Four vanadium compounds will be evaluated in a STZ-induced diabetic rabbit model. Our approach combine Chemical and Biological Experiments to develop superior vanadium compounds for the treatment of diabetes and simultaneously elucidate the mode of action of these compounds. The proposed studies will lead to an in-depth understanding of both the chemical and pharmacological properties of known and new vanadium compounds inducing insulin-like action.

鉴于最近使用口服有机钒(IV)(KP-102)治疗糖尿病的第一阶段临床试验，钒化合物的胰岛素活性目前引起了极大的兴趣。有机钒化合物在胰岛素样作用和较低的毒性方面优于简单的钒盐(钒酸盐和钒硫酸盐)。这项提议有两个目标。一个目标是描述两种不同类型的有机钒化合物的作用模式。第二个目标是寻找具有优异的胰岛素样活性和较低毒性的新的钒化合物。关于钒化合物如何产生胰岛素增强作用的传统观点是通过抑制作用于胰岛素受体和/或胰岛素信号通路中受体远端的酪氨酸蛋白磷酸酶来实现的。由于没有关于化合物在动物身上的疗效和抑制蛋白磷酸酶的相关性的报道，而且认识到现有的数据量，此时适当地考虑这样的假设，即没有一个目标足以描述钒化合物的作用模式。本文提出的多因素方法是在蛋白质磷酸酶抑制和其他一些未知参数(S)共同作用的前提下发展起来的。要对化合物效应进行系统的多因素机理分析，需要将效应按类别(类胰岛素、毒性、药理学、细胞环境和化学性质)组织起来，每个类别都包含化合物图谱框架中的几个参数。新化合物的设计(目标1)将被用作检验机械假说的工具，这些假说将根据11次化验(目标2)获得的数据而开发。此外，通过组合合成制备的化合物文库将使用4种体外和细胞试验进行筛选，以确定更好的化合物(目标2)。对每个化合物/组合文库的性能进行迭代评估将导致关键结构单元的确定。最后，化合物概况将指导选择四种化合物进行详细的药代动力学和分布分析(目标3)。我们提出的具体目标是：目标1.单个钒化合物和组合钒化合物文库的制备。将对生物活性化合物的水解和氧化还原化学进行表征。目的2.评价钒化合物在体外生物系统(A部分，磷酸酶抑制、蛋白质相互作用、亲脂性和细胞还原剂的作用)、细胞培养(B部分，细胞生长和活力、细胞中钒化合物的形态、正常细胞和钒化合物处理细胞对胰岛素受体磷酸化的刺激)以及对正常和STZ诱导的糖尿病大鼠的作用(C部分，降低血糖水平、胰岛素敏感性、血清总钒稳态吸收和胰岛素受体磷酸化的作用)。目的3.有机钒化合物的药代动力学和分布特征。四种钒化合物将在链脲佐菌素诱导的糖尿病兔模型中进行评估。我们的方法结合化学和生物实验来开发用于治疗糖尿病的优质钒化合物，并同时阐明这些化合物的作用模式。拟议的研究将导致深入了解诱导胰岛素样作用的已知和新的钒化合物的化学和药理学特性。