Matrix Metalloproteinase 13 Inhibitors for Modulation of Osteoclastogenesis: Enhancement of Solubility and Stability.
Matrix Metalloproteinase 13 Inhibitors for Modulation of Osteoclastogenesis: Enhancement of Solubility and Stability.
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DOI：
10.1002/cmdc.202000911
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发表时间：
2021-04-08
期刊：
影响因子：
3.4
通讯作者：
Fields GB
中科院分区：
文献类型：
--
作者：
Knapinska AM;Singh C;Drotleff G;Blanco D;Chai C;Schwab J;Herd A;Fields GB
基质金属蛋白酶13(MMP13)活性与乳腺癌骨转移密切相关。已有研究表明，基质金属蛋白酶-13可能通过促进破骨细胞生成而促进骨转移。为了探讨基质金属蛋白酶-13的作用机制，我们先前报道了一种高效、选择性的基质金属蛋白酶-13抑制剂RF036。不幸的是，由于抑制物的溶解性和稳定性有限，进一步寻求RF036作为体内外活性的探针是不现实的。本研究探索了取代RF036主链硫原子和末端甲基，以创造更有利的药代动力学特性的抑制剂。将RF036的主链硫和末端甲基分别用氮气和氧杂环己烷取代的化合物3具有与RF036相当的活性、选择性和膜透过性，但其溶解性和稳定性大大提高。抑制物3有效地抑制了基质金属蛋白酶-13介导的破骨细胞的形成，但避免了胶原蛋白的溶解，因此代表了一种适用于乳腺癌体内转移研究的新一代基质金属蛋白酶-13探针。基质金属蛋白酶13(MMP13)抑制剂的开发常常受到产物PK性质不佳的影响。本研究试图改善RF036的PK特性，RF036是一种先前描述的选择性基质金属蛋白酶-13抑制剂。抑制物3具有比RF036更好的PK特性，是一种有效的破骨细胞生成抑制物，破骨细胞生成是乳腺癌转移到骨的关键过程。
Matrix metalloproteinase 13 (MMP-13) activity has been correlated to breast cancer bone metastasis. It has been proposed that MMP-13 contributes to bone metastasis via promotion of osteoclastogeneis. To explore the mechanisms of MMP-13 action, we previously described a highly efficacious and selective MMP-13 inhibitor, RF036. Unfortunately, further pursuit of RF036 as a probe of MMP-13 in vitro and in vivo activities was not practical due to the limited solubility and stability of the inhibitor. The present study has explored replacement of the RF036 backbone sulfur atom and terminal methyl group to create inhibitors with more favorable pharmacokinetic properties. One compound, designated inhibitor 3, in which the backbone sulfur and terminal methyl group of RF036 were replaced by nitrogen and oxetane, respectively, had comparable activity, selectivity, and membrane permeability to RF036 while exhibiting greatly enhanced solubility and stability. Inhibitor 3 effectively inhibited MMP-13-mediated osteoclastogenesis but spared collagenolysis, and thus represents a next generation MMP-13 probe applicable for in vivo studies of breast cancer metastasis. The development of matrix metalloproteinase 13 (MMP-13) inhibitors has often been marred by poor PK properties of resulting compounds. The present study has sought to improve the PK properties of RF036, a previously described selective MMP-13 inhibitor. Inhibitor 3 had more favorable PK properties than RF036 and was an effective inhibitor of osteoclastogenesis, a critical process that occurs during breast cancer metastasis to the bone.
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