†Department of Chemistry and Biochemistry, ‡Freimann Life Sciences Center and Department of Biological Sciences, University of Notre Dame , Notre Dame, Indiana 46556, United States.
J Med Chem. 2013 Oct 24;56(20):8139-50. doi: 10.1021/jm401217d. Epub 2013 Oct 8.
Brain metastasis occurs in 20-40% of cancer patients. Treatment is mostly palliative, and the inability of most drugs to penetrate the brain presents one of the greatest challenges in the development of therapeutics for brain metastasis. Matrix metalloproteinase-2 (MMP-2) plays important roles in invasion and vascularization of the central nervous system and represents a potential target for treatment of brain metastasis. Carbonate, O-phenyl carbamate, urea, and N-phenyl carbamate derivatives of SB-3CT, a selective and potent gelatinase inhibitor, were synthesized and evaluated. The O-phenyl carbamate and urea variants were selective and potent inhibitors of MMP-2. Carbamate 5b was metabolized to the potent gelatinase inhibitor 2, which was present at therapeutic concentrations in the brain. In contrast, phenyl urea 6b crossed the blood-brain barrier, however, higher doses would result in therapeutic brain concentrations. Carbamate 5b and urea 6b show potential for intervention of MMP-2-dependent diseases such as brain metastasis.
脑转移发生在 20-40%的癌症患者中。治疗主要是姑息性的，大多数药物无法穿透大脑，这是开发脑转移治疗方法的最大挑战之一。基质金属蛋白酶-2（MMP-2）在中枢神经系统的侵袭和血管生成中发挥重要作用，是治疗脑转移的潜在靶点。SB-3CT 是一种选择性和有效的明胶酶抑制剂，其碳酸酯、O-苯甲酰基氨基甲酸酯、尿素和 N-苯甲酰基氨基甲酸酯衍生物被合成并进行了评估。O-苯甲酰基氨基甲酸酯和尿素变体对 MMP-2 具有选择性和高活性抑制作用。氨基甲酸酯 5b 代谢为强效明胶酶抑制剂 2，其在大脑中存在治疗浓度。相比之下，苯甲酰基脲 6b 能穿过血脑屏障，但更高剂量将导致治疗性脑浓度。氨基甲酸酯 5b 和脲 6b 显示出干预 MMP-2 依赖性疾病（如脑转移）的潜力。
