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Optimization of Hydroxyethylamine Transition State Isosteres as Aspartic Protease Inhibitors by Exploiting Conformational Preferences
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-11-28 00:00:00 , DOI: 10.1021/acs.jmedchem.7b01304 Ana B. Bueno 1 , Javier Agejas 1 , Howard Broughton 1 , Robert Dally 2 , Timothy B. Durham 2 , Juan Félix Espinosa 1 , Rosario González 1 , Patric J. Hahn 2 , Alicia Marcos 1 , Ramón Rodríguez 1 , Gema Sanz 1 , José F. Soriano 1 , David Timm 2 , Paloma Vidal 1 , Hsiu-Chiung Yang 2 , James R. McCarthy 2
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-11-28 00:00:00 , DOI: 10.1021/acs.jmedchem.7b01304 Ana B. Bueno 1 , Javier Agejas 1 , Howard Broughton 1 , Robert Dally 2 , Timothy B. Durham 2 , Juan Félix Espinosa 1 , Rosario González 1 , Patric J. Hahn 2 , Alicia Marcos 1 , Ramón Rodríguez 1 , Gema Sanz 1 , José F. Soriano 1 , David Timm 2 , Paloma Vidal 1 , Hsiu-Chiung Yang 2 , James R. McCarthy 2
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NMR conformational analysis of a hydroxyethylamine peptide isostere developed as an aspartic protease inhibitor shows that it is a flexible architecture. Cyclization to form pyrrolidines, piperidines, or morpholines results in a preorganization of the whole system in solution. The resulting conformation is similar to the conformation of the inhibitor in the active site of BACE-1. This entropic gain results in increased affinity for the enzyme when compared with the acyclic system. For morpholines 27 and 29, the combination of steric and electronic factors is exploited to orient substituents toward S1, S1′, and S2′ pockets both in the solution and in the bound states. These highly preorganized molecules proved to be the most potent compounds of the series. Additionally, the morpholines, unlike the pyrrolidine and piperidine analogues, have been found to be brain penetrant BACE-1 inhibitors.
中文翻译：
利用构象偏好优化羟乙基胺过渡态等位基因作为天冬氨酸蛋白酶抑制剂的优化
对开发为天冬氨酸蛋白酶抑制剂的羟乙胺肽等排物的NMR构象分析表明，它是一种灵活的结构。环化形成吡咯烷，哌啶或吗啉会导致整个系统在溶液中发生预组织。所得的构象类似于抑制剂在BACE-1活性位点的构象。与无环系统相比，这种熵增加导致对酶的亲和力增加。对于吗啉27和29，利用空间因素和电子因素的组合来使取代基在溶液中和在键合状态下都朝向S1，S1'和S2'口袋取向。这些高度预组织的分子被证明是该系列中最有效的化合物。另外，与吡咯烷和哌啶类似物不同，吗啉是脑渗透BACE-1抑制剂。
更新日期：2017-11-28
中文翻译：
利用构象偏好优化羟乙基胺过渡态等位基因作为天冬氨酸蛋白酶抑制剂的优化
对开发为天冬氨酸蛋白酶抑制剂的羟乙胺肽等排物的NMR构象分析表明，它是一种灵活的结构。环化形成吡咯烷，哌啶或吗啉会导致整个系统在溶液中发生预组织。所得的构象类似于抑制剂在BACE-1活性位点的构象。与无环系统相比，这种熵增加导致对酶的亲和力增加。对于吗啉27和29，利用空间因素和电子因素的组合来使取代基在溶液中和在键合状态下都朝向S1，S1'和S2'口袋取向。这些高度预组织的分子被证明是该系列中最有效的化合物。另外，与吡咯烷和哌啶类似物不同，吗啉是脑渗透BACE-1抑制剂。
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