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

描述（由申请人提供）：在美国，估计有130万人，特别是女性，患有类风湿性关节炎（RA）。目前，非甾体抗炎药被用于缓解症状，而抗风湿药物（DMARDs）被用于缓解症状。然而，这些治疗方法并不令人满意，价格昂贵（对于基于蛋白质的dmard），并且通常伴有潜在的严重副作用。在过去的二十年中，对类风湿关节炎的潜在免疫性质的生物学理解的积累为使用新的小分子来更好地治疗类风湿关节炎提供了希望。我们最近发现，一种新的维生素D3 （VD3）代谢物20S-羟基维生素D3 （20S(OH)D3）在体内对类风湿性关节炎非常有效，即使在非常高的剂量下也不会导致高钙血症或其他可检测到的毒性。在这项探索性资助中，我们提议验证我们的总体假设，即这种独特的20-羟基支架所提供的抗RA强效分离和无高钙血症是由于免疫细胞中VDR的选择性转录激活，而不是肠细胞。这种组织的选择性，而不是

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.