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Bioorg Med Chem Lett. 2013 Nov 1;23(21):5949-52. doi: 10.1016/j.bmcl.2013.08.076. Epub 2013 Aug 24.
We have synthesized a novel vitamin D receptor agonist VS-105 ((1R,3R)-5-((E)-2-((3αS,7αS)-1-((R)-1-((S)-3-hydroxy-2,3-dimethylbutoxy)ethyl)-7α-methyldihydro-1H-inden-4(2H,5H,6H,7H,7αH)-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol). Preparation of a-ring phenylphosphine oxide 11, followed by Wittig-Horner coupling of 11 with the protected 25-hydroxy Grundmann's ketone 22 generated the precursor 12. Deprotection of the TBDMS groups of 12 produced the target compound VS-105. The biological profiles of VS-105 were evaluated using in vitro assays (VDR receptor binding, VDR reporter gene and HL-60 differentiation) in comparison to calcitriol (the endogenous hormone) or paricalcitol. Furthermore, the PTH suppressing potency and hypercalcemic side effects of VS-105 were evaluated in the 5/6 nephrectomized uremic rats in comparison to paricalcitol. Combining various changes at 20-epi, 22-oxa, 24-methyl, and 2-methylene yielded VS-105 that not only is highly potent in inducing functional responses in vitro, but also effectively suppresses PTH in a dose range that does not affect serum calcium in the 5/6 nephrectomized uremic rats.
我们合成了一种新型维生素 D 受体激动剂 VS-105((1R,3R)-5-((E)-2-((3αS,7αS)-1-((R)-1-((S)-3-羟基-2,3-二甲基丁氧基)乙基)-7α-甲基二氢-1H-茚-4(2H,5H,6H,7H,7αH)-亚基)亚乙基)-2-亚甲基环己烷-1,3-二醇)。制备 a-环苯基氧化膦 11，然后用保护的 25-羟基 Grundmann 酮 22 对其进行 Wittig-Horner 偶联，生成前体 12。脱除 12 的 TBDMS 基团得到目标化合物 VS-105。通过体外试验（VDR 受体结合、VDR 报告基因和 HL-60 分化）评估 VS-105 的生物学特征，并与骨化三醇（内源性激素）或帕立骨化醇进行比较。此外，在 5/6 肾切除尿毒症大鼠中评估 VS-105 的 PTH 抑制作用和高钙血症副作用，并与帕立骨化醇进行比较。在 20-表、22-氧代、24-甲基和 2-亚甲基上进行各种改变，得到了 VS-105，它不仅在体外诱导功能反应方面具有很高的活性，而且在不影响 5/6 肾切除尿毒症大鼠血清钙的剂量范围内有效抑制 PTH。
