Smith Amos B, Cantin Louis-David, Pasternak Alexander, Guise-Zawacki Lisa, Yao Wenquin, Charnley Adam K, Barbosa Joseph, Sprengeler Paul A, Hirschmann Ralph, Munshi Sanjeev, Olsen David B, Schleif William A, Kuo Lawrence C
Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia, Pennsylvania 19104, USA.
J Med Chem. 2003 May 8;46(10):1831-44. doi: 10.1021/jm0204587.
The design, synthesis, and biological evaluation of a series of HIV-1 protease inhibitors [(-)-6, (-)-7, (-)-23, (+)-24] based upon the 3,5,5-trisubstituted pyrrolin-4-one scaffold is described. Use of a monopyrrolinone scaffold leads to inhibitors with improved cellular transport properties relative to the earlier inhibitors based on bispyrrolinones and their peptide counterparts. The most potent inhibitor (-)-7 displayed 13% oral bioavailability in dogs. X-ray structure analysis of the monopyrrolinone compounds cocrystallized with the wild-type HIV-1 protease provided valuable information on the interactions between the inhibitors and the HIV-1 enzyme. In each case, the inhibitors assumed similar orientations for the P2'-P1 substituents, along with an unexpected hydrogen bond of the pyrrolinone NH with Asp225. Interactions with the S2 pocket, however, were not optimal, as illustrated by the inclusion of a water molecule in two of the three inhibitor-enzyme complexes. Efforts to increase affinity by displacing the water molecule with second and third generation inhibitors did not prove successful. Lack of success with this venture is a testament to the difficulty of accurately predicting the many variables that influence and build binding affinity. Comparison of the inhibitor positions in three complexes with that of Indinavir revealed displacements of the protease backbones in the enzyme flap region, accompanied by variations in hydrogen bonding to accommodate the monopyrrolinone ring. The binding orientation of the pyrrolinone-based inhibitors may explain their sustained efficacy against mutant strains of the HIV-1 protease enzyme as compared to Indinavir.
描述了基于3,5,5-三取代吡咯啉-4-酮支架的一系列HIV-1蛋白酶抑制剂[(-)-6、(-)-7、(-)-23、(+)-24]的设计、合成及生物学评价。与基于双吡咯啉酮及其肽类似物的早期抑制剂相比，单吡咯啉酮支架的使用产生了具有改善的细胞转运特性的抑制剂。最有效的抑制剂(-)-7在犬类中显示出13%的口服生物利用度。与野生型HIV-1蛋白酶共结晶的单吡咯啉酮化合物的X射线结构分析提供了关于抑制剂与HIV-1酶之间相互作用的有价值信息。在每种情况下，抑制剂的P2'-P1取代基呈现相似的取向，同时吡咯啉酮NH与Asp225形成了意想不到的氢键。然而，与S2口袋的相互作用并不理想，这在三个抑制剂-酶复合物中的两个中表现为包含一个水分子。用第二代和第三代抑制剂取代水分子以增加亲和力的努力并未成功。这项尝试的失败证明了准确预测影响和建立结合亲和力的众多变量的难度。将三种复合物中抑制剂的位置与茚地那韦的位置进行比较，发现在酶瓣区域蛋白酶主链发生了位移，同时氢键也发生了变化以容纳单吡咯啉酮环。基于吡咯啉酮的抑制剂的结合取向可能解释了它们与茚地那韦相比对HIV-1蛋白酶突变株的持续疗效。
