Retinitis pigmentosa (RP) is a form of retinal degeneration affecting a young population with an unmet medical need. Photoreceptor degeneration has been associated with increased guanosine 3′,5′-cyclic monophosphate (cGMP), which reaches toxic levels for photoreceptors. Therefore, inhibitory cGMP analogues attract interest for RP treatments. Here we present the synthesis of dithio-CN03, a phosphorodithioate analogue of cGMP, prepared using the H-phosphonothioate route. Two crystal modifications were identified as a trihydrate and a tetrahydrofuran monosolvates. Dithio-CN03 featured a lower aqueous solubility than its R_P-phosphorothioate counterpart CN03, a drug candidate, and this characteristic might be favorable for sustained-release formulations aimed at retinal delivery. Dithio-CN03 was tested in vitro for its neuroprotective effects in photoreceptor models of RP. The comparison of dithio-CN03 to CN03 and its diastereomer S_P-CN03, and to their phosphate derivative oxo-CN03 identifies dithio-CN03 as the compound with the highest efficacy in neuroprotection and thus as a promising new candidate for the treatment of RP.

中文翻译：

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新改进的 cGMP 类似物可靶向杆状光感受器变性


色素性视网膜炎 (RP) 是一种视网膜变性，影响着医疗需求未得到满足的年轻人。光感受器变性与鸟苷 3',5'-环单磷酸 (cGMP) 增加有关，cGMP 达到对光感受器有毒的水平。因此，抑制性 cGMP 类似物引起了 RP 治疗的兴趣。在此，我们介绍了二硫代-CN03 的合成，二硫代磷酸酯是 cGMP 的类似物，采用 H-硫代膦酸路线制备。两种晶体变体被鉴定为三水合物和四氢呋喃单溶剂化物。二硫代-CN03 的水溶性比其候选药物 R _P -硫代磷酸酯对应物 CN03 更低，这一特性可能有利于针对视网膜递送的缓释制剂。在 RP 光感受器模型中体外测试了二硫代 CN03 的神经保护作用。二硫-CN03 与 CN03 及其非对映异构体 S _P -CN03 以及它们的磷酸酯衍生物 oxo-CN03 的比较表明，二硫-CN03 是具有最高神经保护功效的化合物，因此是一种有前途的新候选物用于治疗 RP。