Institute for Drug Research, The Hebrew University of Jerusalem, School of Pharmacy, P.O. Box 12065, Jerusalem 91120, Israel.
ChemMedChem. 2011 Aug 1;6(8):1471-7. doi: 10.1002/cmdc.201100153. Epub 2011 Jun 8.
Seven 4-phenoxybenzenesulfonamidopolymethylene carbamoylphosphonates (CPOs) bearing two to eight methylene units in the polymethylene chain were synthesized and evaluated as matrix metalloproteinase (MMP) inhibitors. The five lowest homologues [(CH₂)₂-₆] are selective MMP-2 inhibitors, whereas the two with the longest linkers [(CH₂)₇,₈] lack inhibitory activity. The most potent homologues are those with (CH₂)₅,₆; these two were evaluated for antimetastatic activity in a murine melanoma model and showed good potency both by oral and intraperitoneal administration without any toxic--including musculoskeletal--side effects. In contrast to the previously reported cis-ACCP, which was shown to inhibit MMP-2 for ∼30 min, the new compounds inhibit MMP activity for the duration of measurement, lasting several hours. Pharmacokinetic evaluation revealed, on the one hand, low oral bioavailability; on the other hand, a relatively large calculated volume of distribution, consistent with the observed reversible absorption of CPO 5 to hydroxyapatite, as a model for bone.
合成了七种含有两个到八个亚甲基单元的 4-苯氧基苯磺酰胺聚亚甲基碳二亚胺膦酸酯（CPO），并将其评估为基质金属蛋白酶（MMP）抑制剂。五个最低同系物 [(CH₂)₂-₆] 是选择性 MMP-2 抑制剂，而具有最长连接物 [(CH₂)₇,₈] 的两种则缺乏抑制活性。最有效的同系物是那些具有 (CH₂)₅,₆ 的同系物；这两种同系物在黑色素瘤模型中进行了抗转移活性评估，通过口服和腹腔内给药均表现出良好的效力，没有任何毒性——包括肌肉骨骼——副作用。与先前报道的 cis-ACCP 相反，cis-ACCP 被证明可以抑制 MMP-2 约 30 分钟，而新化合物可以在测量时间内抑制 MMP 活性，持续数小时。药代动力学评估显示，一方面，口服生物利用度低；另一方面，计算出的分布体积相对较大，与观察到的 CPO5 可逆吸收到羟磷灰石（作为骨的模型）一致。
