Discovery of tissue-selective, nonhypercalcemic VDR modulators for RA treatment

发现用于 RA 治疗的组织选择性、非高钙血症 VDR 调节剂

• 批准号: 8511162
• 负责人: WEI LI
• 金额: $ 15.94万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8511162
• 关键词: 25-hydroxycholecalciferol-24-hydroxylase; Adrenal Cortex Hormones; Adverse effects; Aging; Agonist; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Autoimmune Diseases; Bacteria; Biological; Blood; Caco-2 Cells; Cells; Cessation of life; Cholecalciferol; Chronic Disease; Collagen Arthritis; Disease remission; Disease-Modifying Second-Line Drugs; Dose; Drug Design; Drug usage; Future; Genes; Goals; Grant; Human; Hypercalcemia; Immune; Immune System Diseases; In Vitro; Inflammation; Intestines; Jurkat Cells; Lead; Life Expectancy; Literature; Methods; Modeling; Molecular Models; Nature; Non-Steroidal Anti-Inflammatory Agents; Nuclear Receptors; Organ failure; Population; Positioning Attribute; Preclinical Testing; Proteins; Receptor Activation; Research; Rheumatoid Arthritis; Secondary to; Selective Estrogen Receptor Modulators; Side; Skin; Small Intestines; Stereoisomer; Stroke; Structure-Activity Relationship; Symptoms; T-Lymphocyte; Testing; Therapeutic; Tissues; Toxic effect; Transcriptional Activation; Translating; Ulcer; Virus Diseases; Vitamin D; Vitamin D3 Receptor; Woman; analog; base; calcium absorption; design; drug development; effective therapy; high reward; high risk; improved; in vitro testing; in vivo; indexing; inflammatory marker; molecular modeling; novel; public health relevance; scaffold; selective androgen receptor modulator; selective expression; small molecule; success; viral leukemia

DESCRIPTION (provided by applicant): An estimated 1.3 million people in the US, especially women, suffer from rheumatoid arthritis (RA). Currently NSAIDs are used to relieve symptoms, and disease-modifying antirheumatic drugs (DMARDs) are used to produce remissions. However, these treatments are not satisfactory, prohibitively expensive (for protein based DMARDs), and often associated with potentially severe side effects. Biological understanding of the underline immune nature of RA accumulated in the last two decades have provided promises in using novel small molecules for better treatment of RA. We recently discovered that a novel class of vitamin D3 (VD3) metabolites, 20S-hydroxyvitamin D3 (20S(OH)D3), is highly efficacious against RA in vivo without resulting hypercalcemia or other detectable toxicities, even at very high doses. In this exploratory grant, we propose to test our overall hypothesis that the observed separation in strong efficacy against RA and the absence of hypercalcemia provided by this unique 20-hydroxy scaffold is due to the selective transcriptional activation of VDR in immune cells compared to intestine cells. This tissue selectivity, rather than the absolute potency of VDR activation, holds a new paradigm for developing clinically useful VD3 modulators for improved RA treatment. We have recently developed stereospecific synthetic methods to make new analogs. Some of these analogs show very promising anti-inflammation activities, at least comparable to that of 20S(OH)D3. Clearly there is room for further structural optimization based on 20S(OH)D3. Therefore, our objective is to develop several orally active, highly tissue-selective, VDR modulators based on this unique 20-hydroxyscaffold. Our specific aims are: (1) To test the hypothesis that the anti-inflammatory potency of 20S(OH)D3 can be further optimized with rational drug design. We will screen newly synthesized analogs against established markers for inflammation and use the structure-activity relationships (SAR) to guide iterative optimization for their anti-inflammatory activity. (2) To tst the hypothesis that the mechanism of action of the optimized highly active 20(OH)D3 analogs will selectively activate VDR in immune cells compared to intestine cells and that the in vitro selectivity observed will translate to in vivo efficacy for RA. We will test the hypotheses that (a they will activate VDR differentially in immune cells compared to intestine cells; (b) they will induce selective expression of key VDR- responsive genes in immune cells compared to intestine cells; (c) they will suppress RA efficiently without hypercalcemia using the well-established collagen induced arthritis (CIA) model. Our long term goal for this research is to develop novel classes of highly tissue-selective VDR modulators for immune cells compared to the intestine cells. Success in developing such agents will not only have high impact for RA, but will also have significant impact in treating many other autoimmune diseases.

描述（由申请人提供）：估计有130万人，尤其是妇女，患有类风湿关节炎（RA）。目前，NSAID用于缓解症状，调整抗病药物（DMARDS）用于产生缓解。但是，这些治疗方法并不令人满意，昂贵（对于基于蛋白质的DMARD），并且通常与潜在的严重副作用有关。对过去二十年中RA的下划线免疫性质的生物学理解为使用新型的小分子以更好地治疗RA提供了承诺。 我们最近发现，一种新型的维生素D3（VD3）代谢产物，20S-羟基维生素D3（20S（OH）D3），即使在非常高剂量的情况下，也没有导致过度过钙或其他可检测的毒性，也没有导致过度过钙或其他可检测的毒性，对体内的RA具有高效。在这项探索性赠款中，我们建议测试我们的总体假设，即观察到的针对RA的强疗法的分离以及与肠细胞相比，这种独特的20-羟基支架所提供的高钙血症是由于Immune细胞中VDR的选择性转录激活所致。这种组织选择性，而不是 VDR激活的绝对效力具有一个新的范式，用于开发临床上有用的VD3调节剂，以改善RA处理。我们最近开发了立体特异性的合成方法来制作新的类似物。其中一些类似物显示出非常有希望的抗炎活性，至少与20s（OH）D3相当。显然，基于20S（OH）D3，还有进一步的结构优化空间。因此，我们的目标是基于这个独特的20-羟基含量，开发几种口服活性，高组织选择性的VDR调节剂。 我们的具体目的是：（1）检验以下假设：20S（OH）D3的抗炎效力可以通过合理的药物设计进一步优化。我们将筛选新合成的类似物对炎症的已建立标记，并使用结构活性关系（SAR）指导其抗炎活性的迭代优化。 （2）提出一个假说，即优化的高度活性20（OH）D3类似物的作用机理将选择性地激活免疫细胞中的VDR，并且与肠细胞相比，观察到的体外选择性将转化为RA的体内功效。我们将测试以下假设：与肠细胞相比，与肠细胞相比，它们将在免疫细胞中激活VDR；（b）它们将诱导免疫细胞中关键的VDR响应基因的选择性表达与肠细胞相比；（c）它们将在没有高度良好的胶原蛋白诱导的cia（cia）中进行高度攻击（CIA），而无需高度降低了高度症（CA），这是我们的长期研究（CIA）的模型。与肠道细胞相比，免疫细胞的VDR调节剂不仅对RA产生了很高的影响，而且还将对许多其他自身免疫性疾病产生重大影响。