Identification of 3-aminomethyl-1,2-dihydro-4-phenyl-1-isoquinolones: A new class of potent, selective, and orally active non-peptide dipeptidyl peptidase IV inhibitors that form a unique interaction with Lys554
Identification of 3-aminomethyl-1,2-dihydro-4-phenyl-1-isoquinolones: A new class of potent, selective, and orally active non-peptide dipeptidyl peptidase IV inhibitors that form a unique interaction with Lys554
复制标题
DOI：
10.1016/j.bmc.2011.06.059
复制
发表时间：
2011-08-15
影响因子：
3.5
通讯作者：
Maezaki, Hironobu
中科院分区：
文献类型：
--
作者：
Banno, Yoshihiro;Miyamoto, Yasufumi;Maezaki, Hironobu
介绍了一类新型有效的口服活性非肽基二肽基多肽酶IV抑制剂3-aminomethyl-1，2-dihydro-4-phenyl-1-isoquinolones，的设计、合成及其构效关系。我们假设异喹诺酮的4-苯基占据了酶的S1口袋，3-氨甲基与S2口袋形成静电相互作用，而在6-或7-取代基上引入氢键供体提供了与酶的亲水性区域的相互作用。基于这一假设，人们对开发新的非肽DPP-4抑制剂进行了深入的研究。在本研究设计的化合物中，我们确认2-[(3-aminomethyl-2-(2-methylpropyl)-1-oxo-4-phenyl-1，2-dihydro-6-isoquinolinyl)氧基乙酰胺(35a)是一种有效的、选择性的、口服生物利用的DPP-4抑制剂，在糖尿病模型大鼠中显示出体内疗效。最后，35a与该酶的络合物中的X射线结晶学验证了我们假设的结合模式，并确认Lys554是DPP-4抑制剂可用的新的靶向结合位点。(C)2011爱思唯尔有限公司。保留所有权利。
The design, synthesis, and structure-activity relationships of a new class of potent and orally active non-peptide dipeptidyl peptidase IV (DPP-4) inhibitors, 3-aminomethyl-1,2-dihydro-4-phenyl-1-isoquinolones, are described. We hypothesized that the 4-phenyl group of the isoquinolone occupies the S1 pocket of the enzyme, the 3-aminomethyl group forms an electrostatic interaction with the S2 pocket, and the introduction of a hydrogen bond donor onto the 6- or 7-substituent provides interaction with the hydrophilic region of the enzyme. Based on this hypothesis, intensive research focused on developing new non-peptide DPP-4 inhibitors has been carried out. Among the compounds designed in this study, we identified 2-[(3-aminomethyl-2-(2-methylpropyl)-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl) oxy] acetamide (35a) as a potent, selective, and orally bioavailable DPP-4 inhibitor, which exhibited in vivo efficacy in diabetic model rats. Finally, X-ray crystallography of 35a in a complex with the enzyme validated our hypothesized binding mode and identified Lys554 as a new target-binding site available for DPP-4 inhibitors. (C) 2011 Elsevier Ltd. All rights reserved.