A Non-Systemic Phosphodiesterase-5 Inhibitor Suppresses Colon Proliferation in Mice.
A Non-Systemic Phosphodiesterase-5 Inhibitor Suppresses Colon Proliferation in Mice.
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DOI：
10.3390/ijms24119397
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发表时间：
2023-05-28
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
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作者：
磷酸二酯酶-5抑制剂（PDE 5i）正在研究用于结肠癌预防。常规PDE 5i的缺点是它们的副作用和药物-药物相互作用。我们设计了一种原型PDE 5i西地那非的类似物，通过用丙二酸取代哌嗪环上的甲基以降低亲脂性，并测量其进入循环和对结肠上皮的影响。这种修饰不影响药理学，因为丙二酰-西地那非的IC 50与西地那非相似，但增加细胞cGMP的EC 50降低近20倍。使用LC-MS/MS方法，经口给药后，小鼠血浆中的丙二酰-西地那非可忽略不计，但在粪便中检测到高水平。通过测量与单硝酸异山梨酯的相互作用，在循环中未检测到丙二酰-西地那非的生物活性代谢产物。在饮用水中用丙二酰-西地那非处理小鼠导致结肠上皮细胞增殖抑制，这与先前发表的用PDE 5i处理小鼠的结果一致。含羧酸的西地那非类似物可抑制化合物的全身给药，但仍能充分渗透到结肠上皮细胞中以抑制增殖。这突出了一种新的方法来产生一流的药物用于结肠癌化学预防。
Phosphodiesterase-5 inhibitors (PDE5i) are under investigation for repurposing for colon cancer prevention. A drawback to conventional PDE5i are their side-effects and drug–drug interactions. We designed an analog of the prototypical PDE5i sildenafil by replacing the methyl group on the piperazine ring with malonic acid to reduce lipophilicity, and measured its entry into the circulation and effects on colon epithelium. This modification did not affect pharmacology as malonyl-sildenafil had a similar IC50 to sildenafil but exhibited an almost 20-fold reduced EC50 for increasing cellular cGMP. Using an LC-MS/MS approach, malonyl-sildenafil was negligible in mouse plasma after oral administration but was detected at high levels in the feces. No bioactive metabolites of malonyl-sildenafil were detected in the circulation by measuring interactions with isosorbide mononitrate. The treatment of mice with malonyl-sildenafil in the drinking water resulted in a suppression of proliferation in the colon epithelium that is consistent with results previously published for mice treated with PDE5i. A carboxylic-acid-containing analog of sildenafil prohibits the systemic delivery of the compound but maintains sufficient penetration into the colon epithelium to suppress proliferation. This highlights a novel approach to generating a first-in-class drug for colon cancer chemoprevention.
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DOI：
10.1158/1940-6207.capr-17-0015
发表时间：
2017-07
期刊：
Cancer prevention research (Philadelphia, Pa.)
影响因子：
--
作者：
Islam BN;Sharman SK;Hou Y;Bridges AE;Singh N;Kim S;Kolhe R;Trillo-Tinoco J;Rodriguez PC;Berger FG;Sridhar S;Browning DD
通讯作者：
Browning DD
影响因子：
29.4
作者：
Huang, Wuqing;Sundquist, Jan;Ji, Jianguang
通讯作者：
Ji, Jianguang
影响因子：
4.7
作者：
Islam, Bianca N.;Sharman, Sarah K.;Browning, Darren D.
通讯作者：
Browning, Darren D.
影响因子：
3.5
作者：
Kim, DK;Lee, N;Lee, K
通讯作者：
Lee, K
DOI：
10.1016/s0731-7085(03)00088-8
发表时间：
2003-06-01
影响因子：
3.4
作者：
Kim, J;Ji, HY;Lee, HS
通讯作者：
Lee, HS