Potent and selective α-ketoheterocycle-based inhibitors of the anandamide and oleamide catabolizing enzyme, fatty acid amide hydrolase
Potent and selective α-ketoheterocycle-based inhibitors of the anandamide and oleamide catabolizing enzyme, fatty acid amide hydrolase
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DOI：
10.1021/jm0611509
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发表时间：
2007-03-08
影响因子：
7.3
通讯作者：
Boger, Dale L.
中科院分区：
文献类型：
--
作者：
Romero, F. Anthony;Du, Wu;Boger, Dale L.
以恶唑的5位为靶点，对脂肪酸酰胺水解酶（FAAH）抑制剂2f（OL-135）的构效关系进行了研究。对一系列取代的苯衍生物（12-14）的检测表明，取代的最佳位置是间位，所选成员接近或超过2f的效力。与这些研究同时，还研究了取代对2f的吡啶环的影响。还探索了一系列小的非芳族C5-取代基，并揭示了Ki遵循与Hammett σ（p）常数（rho = 3.01，R2 = 0.91）的明确定义的相关性，其中吸电子取代基增强效力，导致抑制剂的Ki低至400 pM（20 η）。对抑制剂的蛋白质组学范围的筛选显示，大多数对FAAH的选择性超过所有其他哺乳动物蛋白酶，逆转了20 a（C5取代基= H）对TGH酶的100倍偏好。
A study of the structure-activity relationships (SAR) of 2f (OL-135), a potent inhibitor of fatty acid amide hydrolase (FAAH), is detailed, targeting the 5-position of the oxazole. Examination of a series of substituted benzene derivatives (12-14) revealed that the optimal position for substitution was the meta-position with selected members approaching or exceeding the potency of 2f. Concurrent with these studies, the effect of substitution on the pyridine ring of 2f was also examined. A series of small, nonaromatic C5-substituents was also explored and revealed that the K-i follows a well-defined correlation with the Hammett sigma(p) constant (rho = 3.01, R-2 = 0.91) in which electron-withdrawing substituents enhance potency, leading to inhibitors with K(i)s as low as 400 pM (20n). Proteomic-wide screening of the inhibitors revealed that most are exquisitely selective for FAAH over all other mammalian proteases, reversing the 100-fold preference of 20a (C5 substituent = H) for the enzyme TGH.