Kaldor S W, Kalish V J, Davies J F, Shetty B V, Fritz J E, Appelt K, Burgess J A, Campanale K M, Chirgadze N Y, Clawson D K, Dressman B A, Hatch S D, Khalil D A, Kosa M B, Lubbehusen P P, Muesing M A, Patick A K, Reich S H, Su K S, Tatlock J H
Agouron Pharmaceuticals, Inc., San Diego, California 92121, USA.
J Med Chem. 1997 Nov 21;40(24):3979-85. doi: 10.1021/jm9704098.
Using a combination of iterative structure-based design and an analysis of oral pharmacokinetics and antiviral activity, AG1343 (Viracept, nelfinavir mesylate), a nonpeptidic inhibitor of HIV-1 protease, was identified. AG1343 is a potent enzyme inhibitor (Ki = 2 nM) and antiviral agent (HIV-1 ED50 = 14 nM). An X-ray cocrystal structure of the enzyme-AG1343 complex reveals how the novel thiophenyl ether and phenol-amide substituents of the inhibitor interact with the S1 and S2 subsites of HIV-1 protease, respectively. In vivo studies indicate that AG1343 is well absorbed orally in a variety of species and possesses favorable pharmacokinetic properties in humans. AG1343 (Viracept) has recently been approved for marketing for the treatment of AIDS.
通过结合基于结构的迭代设计以及口服药代动力学和抗病毒活性分析，确定了HIV-1蛋白酶的非肽类抑制剂AG1343（维乐命，甲磺酸奈非那韦）。AG1343是一种强效酶抑制剂（Ki = 2 nM）和抗病毒剂（HIV-1 ED50 = 14 nM）。酶-AG1343复合物的X射线共晶体结构揭示了抑制剂的新型硫代苯基醚和酚酰胺取代基分别如何与HIV-1蛋白酶的S1和S2亚位点相互作用。体内研究表明，AG1343在多种物种中口服吸收良好，在人体中具有良好的药代动力学特性。AG1343（维乐命）最近已获批准上市用于治疗艾滋病。
