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

描述（由申请人提供）：美国估计有130万人，尤其是女性，患有类风湿性关节炎（RA）。目前，NSAID用于缓解症状，疾病缓解抗风湿药物（DMARD）用于缓解症状。然而，这些治疗并不令人满意，过于昂贵（对于基于蛋白质的DMARD），并且通常与潜在的严重副作用相关。在过去的二十年中积累的RA的强调免疫性质的生物学理解提供了使用新的小分子更好地治疗RA的承诺。 我们最近发现，一类新的维生素D3（VD 3）代谢物，20 S-羟基维生素D3（20 S（OH）D3），是非常有效的抗RA在体内不会导致高钙血症或其他可检测到的毒性，即使在非常高的剂量。在这项探索性资助中，我们建议测试我们的总体假设，即观察到的这种独特的20-羟基支架对RA的强效分离和不存在高钙血症是由于与肠细胞相比，免疫细胞中VDR的选择性转录激活。这种组织选择性，而不是 VDR激活的绝对效力，为开发用于改善RA治疗的临床上有用的VD 3调节剂提供了新的范例。我们最近开发了立体特异性合成方法来制备新的类似物。这些类似物中的一些显示出非常有希望的抗炎活性，至少与20 S（OH）D3相当。显然，存在基于20 S（OH）D3的进一步结构优化的空间。因此，我们的目标是基于这种独特的20-羟基支架开发几种口服活性的、高组织选择性的VDR调节剂。 我们的具体目标是：（1）验证20 S（OH）D3的抗炎作用可以通过合理的药物设计进一步优化的假设。我们将针对已建立的炎症标志物筛选新合成的类似物，并使用结构-活性关系（SAR）来指导其抗炎活性的迭代优化。 (2)为了验证以下假设：与肠细胞相比，优化的高活性20（OH）D3类似物的作用机制将选择性地激活免疫细胞中的VDR，并且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：（a）与肠细胞相比，它们将在免疫细胞中差异性地激活VDR;（b）与肠细胞相比，它们将诱导免疫细胞中关键VDR响应基因的选择性表达;（B）使用成熟的胶原蛋白诱导的关节炎（CIA）模型，它们将有效抑制RA，而不会出现高钙血症。 我们这项研究的长期目标是开发新型的高组织选择性VDR调节剂，用于免疫细胞，而不是肠细胞。成功开发这种药物不仅对RA有很大的影响，而且对治疗许多其他自身免疫性疾病也有重大影响。

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.