Utilizing structures of CYP2D6 and BACE1 complexes to reduce risk of drug-drug interactions with a novel series of centrally efficacious BACE1 inhibitors.
Utilizing structures of CYP2D6 and BACE1 complexes to reduce risk of drug-drug interactions with a novel series of centrally efficacious BACE1 inhibitors.
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DOI：
10.1021/acs.jmedchem.5b00191
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发表时间：
2015-04-09
影响因子：
7.3
通讯作者：
O'Neill, Brian T.
中科院分区：
文献类型：
--
作者：
Brodney, Michael A.;Beck, Elizabeth M.;Butler, Christopher R.;Barreiro, Gabriela;Johnson, Eric F.;Riddell, David;Parris, Kevin;Nolan, Charles E.;Fan, Ying;Atchison, Kevin;Gonzales, Cathleen;Robshaw, Ashley E.;Doran, Shawn D.;Bundesmann, Mark W.;Buzon, Leanne;Dutra, Jason;Henegar, Kevin;LaChapelle, Erik;Hou, Xinjun;Rogers, Bruce N.;Pandit, Jayvardhan;Lira, Ricardo;Martinez-Alsina, Luis;Mikochik, Peter;Murray, John C.;Ogilvie, Kevin;Price, Loren;Sakya, Subas M.;Yu, Aijia;Zhang, Yong;O'Neill, Brian T.
近年来，第一代β-分泌酶（BACE 1）抑制剂进入临床开发阶段，用于治疗阿尔茨海默病（AD）。然而，药物样性质和选择性的对齐仍然是一个重大挑战。在此，我们描述了一类新的有效的，低清除率，CNS渗透BACE 1抑制剂的硫代脒5代表的发现。进一步分析表明，代谢的很大一部分（>95%）是由于CYP 2D 6，增加了基于受害者的药物相互作用（DDI）的潜在风险，并且由于该酶的多态性，临床暴露量可变。为了指导未来的设计，我们解决了CYP 2D 6与底物5及其相应的代谢产物吡唑6的复合物的晶体结构，这提供了对底物/抑制剂复合物之间的结合模式和运动的洞察。在BACE 1和CYP 2D 6晶体结构的指导下，我们设计并合成了具有降低DDI风险、中心疗效和改善hERG治疗范围的类似物。
In recent years, the first generation of β-secretase (BACE1) inhibitors advanced into clinical development for the treatment of Alzheimer’s disease (AD). However, the alignment of drug-like properties and selectivity remains a major challenge. Herein, we describe the discovery of a novel class of potent, low clearance, CNS penetrant BACE1 inhibitors represented by thioamidine 5. Further profiling suggested that a high fraction of the metabolism (>95%) was due to CYP2D6, increasing the potential risk for victim-based drug–drug interactions (DDI) and variable exposure in the clinic due to the polymorphic nature of this enzyme. To guide future design, we solved crystal structures of CYP2D6 complexes with substrate 5 and its corresponding metabolic product pyrazole 6, which provided insight into the binding mode and movements between substrate/inhibitor complexes. Guided by the BACE1 and CYP2D6 crystal structures, we designed and synthesized analogues with reduced risk for DDI, central efficacy, and improved hERG therapeutic margins.
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DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
3.6
作者：
BURGESS, EM;PENTON, HR;TAYLOR, EA
通讯作者：
TAYLOR, EA
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH
DOI：
10.1039/c39790001180
发表时间：
1979-01-01
影响因子：
--
作者：
DEVOS, A;REMION, J;GHOSEZ, L
通讯作者：
GHOSEZ, L
影响因子：
7.3
作者：
Jamieson, Craig;Moir, Elizabeth M.;Wishart, Grant
通讯作者：
Wishart, Grant