成功的中枢神经系统药物的药用化学性质。
Medicinal chemical properties of successful central nervous system drugs.
作者信息
Pajouhesh Hassan, Lenz George R
机构信息
Department of Medicinal Chemistry, Neuromed Technologies Inc., Vancouver, British Columbia, Canada V6T 1Z4.
出版信息
NeuroRx. 2005 Oct;2(4):541-53. doi: 10.1602/neurorx.2.4.541.
Abstract
Fundamental physiochemical features of CNS drugs are related to their ability to penetrate the blood-brain barrier affinity and exhibit CNS activity. Factors relevant to the success of CNS drugs are reviewed. CNS drugs show values of molecular weight, lipophilicity, and hydrogen bond donor and acceptor that in general have a smaller range than general therapeutics. Pharmacokinetic properties can be manipulated by the medicinal chemist to a significant extent. The solubility, permeability, metabolic stability, protein binding, and human ether-ago-go-related gene inhibition of CNS compounds need to be optimized simultaneously with potency, selectivity, and other biological parameters. The balance between optimizing the physiochemical and pharmacokinetic properties to make the best compromises in properties is critical for designing new drugs likely to penetrate the blood brain barrier and affect relevant biological systems. This review is intended as a guide to designing CNS therapeutic agents with better drug-like properties.
摘要
中枢神经系统药物的基本物理化学特性与其穿透血脑屏障的能力、亲和力及表现出的中枢神经系统活性相关。本文综述了与中枢神经系统药物成功相关的因素。中枢神经系统药物的分子量、亲脂性以及氢键供体和受体的值，总体上比一般治疗药物的范围更小。药物化学家在很大程度上可以操控药代动力学性质。中枢神经系统化合物的溶解度、渗透性、代谢稳定性、蛋白结合以及对人醚 - 去极化相关基因的抑制作用，需要与效力、选择性和其他生物学参数同时进行优化。在优化物理化学和药代动力学性质之间取得平衡，以便在性质上做出最佳折衷，对于设计可能穿透血脑屏障并影响相关生物系统的新药至关重要。本综述旨在作为设计具有更好类药性质的中枢神经系统治疗药物的指南。
相似文献
1
Medicinal chemical properties of successful central nervous system drugs.成功的中枢神经系统药物的药用化学性质。
NeuroRx. 2005 Oct;2(4):541-53. doi: 10.1602/neurorx.2.4.541.
2
CNS drug design: balancing physicochemical properties for optimal brain exposure.中枢神经系统药物设计：平衡理化性质以实现最佳脑内暴露。
J Med Chem. 2015 Mar 26;58(6):2584-608. doi: 10.1021/jm501535r. Epub 2015 Jan 6.
3
On the future development of optimally-sized lipid-insoluble systemic therapies for CNS solid tumors and other neuropathologies.关于中枢神经系统实体瘤和其他神经病理学的最佳尺寸脂溶性全身疗法的未来发展。
Recent Pat CNS Drug Discov. 2010 Nov;5(3):239-52. doi: 10.2174/157488910793362403.
4
Passive permeability and P-glycoprotein-mediated efflux differentiate central nervous system (CNS) and non-CNS marketed drugs.被动通透性和P-糖蛋白介导的外排作用区分了中枢神经系统（CNS）和非中枢神经系统上市药物。
J Pharmacol Exp Ther. 2002 Dec;303(3):1029-37. doi: 10.1124/jpet.102.039255.
5
CNS Physicochemical Property Space Shaped by a Diverse Set of Molecules with Experimentally Determined Exposure in the Mouse Brain.由一组在小鼠脑中具有实验确定暴露量的多样分子塑造的中枢神经系统物理化学性质空间。
J Med Chem. 2017 Jul 27;60(14):5943-5954. doi: 10.1021/acs.jmedchem.6b01469. Epub 2017 Apr 7.
6
Start small and stay small. Minimizing attrition in the clinic with a focus on CNS therapeutics.从小做起，保持小规模。专注于中枢神经系统治疗药物，减少临床流失。
Curr Top Med Chem. 2009;9(18):1688-704. doi: 10.2174/156802609790102374.
7
The blood-brain barrier: bottleneck in brain drug development.血脑屏障：脑药物研发的瓶颈
NeuroRx. 2005 Jan;2(1):3-14. doi: 10.1602/neurorx.2.1.3.
8
Drug metabolism and pharmacokinetics, the blood-brain barrier, and central nervous system drug discovery.药物代谢与药代动力学、血脑屏障及中枢神经系统药物发现
NeuroRx. 2005 Oct;2(4):554-71. doi: 10.1602/neurorx.2.4.554.
9
Moving beyond rules: the development of a central nervous system multiparameter optimization (CNS MPO) approach to enable alignment of druglike properties.超越规则：中枢神经系统多参数优化 (CNS MPO) 方法的开发，以实现类似药物特性的一致性。
ACS Chem Neurosci. 2010 Jun 16;1(6):435-49. doi: 10.1021/cn100008c. Epub 2010 Mar 25.
10
Assessment of the classification abilities of the CNS multi-parametric optimization approach by the method of logistic regression.通过逻辑回归方法评估中枢神经系统多参数优化方法的分类能力。
SAR QSAR Environ Res. 2016 Aug;27(8):629-35. doi: 10.1080/1062936X.2016.1212922. Epub 2016 Aug 1.
引用本文的文献
1
Design, Synthesis, and Molecular Docking Studies of Novel Pyrazoline-Thiazoles as Cholinesterase Dual-Target Inhibitors for the Treatment of Alzheimer's Disease.新型吡唑啉-噻唑类化合物作为胆碱酯酶双靶点抑制剂治疗阿尔茨海默病的设计、合成及分子对接研究
ACS Omega. 2025 Aug 22;10(34):38427-38439. doi: 10.1021/acsomega.5c01055. eCollection 2025 Sep 2.
2
Overcoming the Blood-Brain Barrier: Advanced Strategies in Targeted Drug Delivery for Neurodegenerative Diseases.突破血脑屏障：神经退行性疾病靶向药物递送的先进策略
Pharmaceutics. 2025 Aug 11;17(8):1041. doi: 10.3390/pharmaceutics17081041.
3
In Silico and In Vivo Pharmacological Evaluation of Iridoid Compounds: Geniposide and Asperuloside Profile Study Through Molecular Docking Assay and in the Model.环烯醚萜类化合物的计算机模拟和体内药理学评价：通过分子对接试验和在模型中对栀子苷和车叶草苷的研究
Biomolecules. 2025 Jul 31;15(8):1105. doi: 10.3390/biom15081105.
4
Opportunities for and Challenges of Pulmonary Drug Delivery in the Management of Acute Exacerbations of CNS Disorders.中枢神经系统疾病急性加重期肺部给药的机遇与挑战
CNS Drugs. 2025 Aug 7. doi: 10.1007/s40263-025-01213-4.
5
Antagonistic Trends Between Binding Affinity and Drug-Likeness in SARS-CoV-2 Mpro Inhibitors Revealed by Machine Learning.机器学习揭示的SARS-CoV-2 Mpro抑制剂中结合亲和力与类药性之间的拮抗趋势
Viruses. 2025 Jun 30;17(7):935. doi: 10.3390/v17070935.
6
Differential Modulation of Copper(II) Interactions with the 18-22 Coordinating Amylin Fragment by the Geometric Isomers of a New Nicotinoyl Hydrazone: A First Study.新型烟酰腙的几何异构体对铜（II）与18 - 22个配位的胰岛淀粉样多肽片段相互作用的差异调节：初步研究
ACS Omega. 2025 Jul 11;10(28):31115-31127. doi: 10.1021/acsomega.5c04850. eCollection 2025 Jul 22.
7
Discovery of -(6-Methoxypyridin-3-yl)quinoline-2-amine Derivatives for Imaging Aggregated α-Synuclein in Parkinson's Disease with Positron Emission Tomography.用于正电子发射断层扫描成像帕金森病中聚集的α-突触核蛋白的-(6-甲氧基吡啶-3-基)喹啉-2-胺衍生物的发现
Cells. 2025 Jul 18;14(14):1108. doi: 10.3390/cells14141108.
8
Network pharmacology and molecular dynamics simulation reveal antineoplastic potential of Antarctic sponge-derived suberitenones.网络药理学和分子动力学模拟揭示南极海绵衍生的软海绵酮的抗肿瘤潜力。
Front Chem. 2025 May 27;13:1545834. doi: 10.3389/fchem.2025.1545834. eCollection 2025.
9
Decarboxylative sulfation by persulfates.过硫酸盐介导的脱羧硫酸化反应
Chem Sci. 2025 May 29. doi: 10.1039/d5sc03129j.
10
5'-Guanidino Xylofuranosyl Nucleosides as Novel Types of 5'-Functionalized Nucleosides with Biological Potential.5'-胍基木呋喃糖基核苷作为具有生物活性的新型5'-官能化核苷
Pharmaceuticals (Basel). 2025 May 16;18(5):734. doi: 10.3390/ph18050734.
本文引用的文献
1
Lead- and drug-like compounds: the rule-of-five revolution.类铅化合物和类药物化合物：五规则革命
Drug Discov Today Technol. 2004 Dec;1(4):337-41. doi: 10.1016/j.ddtec.2004.11.007.
2
Cytochrome p450 in silico: an integrative modeling approach.细胞色素P450的计算机模拟：一种综合建模方法。
J Med Chem. 2005 Apr 21;48(8):2725-55. doi: 10.1021/jm040180d.
3
The blood-brain barrier and neurotherapeutics.血脑屏障与神经治疗学
NeuroRx. 2005 Jan;2(1):1-2. doi: 10.1602/neurorx.2.1.1.
4
Time-related differences in the physical property profiles of oral drugs.口服药物物理性质概况的时间相关差异。
J Med Chem. 2004 Dec 2;47(25):6338-48. doi: 10.1021/jm049717d.
5
Constructing optimum blood brain barrier QSAR models using a combination of 4D-molecular similarity measures and cluster analysis.使用4D分子相似性度量和聚类分析相结合的方法构建最佳血脑屏障定量构效关系模型。
J Chem Inf Comput Sci. 2004 Nov-Dec;44(6):2083-98. doi: 10.1021/ci0498057.
6
QT prolongation through hERG K(+) channel blockade: current knowledge and strategies for the early prediction during drug development.通过人乙醚 - 去极化相关基因（hERG）钾离子通道阻滞导致的QT间期延长：药物研发过程中早期预测的现有知识与策略
Med Res Rev. 2005 Mar;25(2):133-66. doi: 10.1002/med.20019.
7
In silico prediction models for blood-brain barrier permeation.血脑屏障通透性的计算机预测模型。
Curr Med Chem. 2004 Jun;11(12):1617-28. doi: 10.2174/0929867043365071.
8
The many roles of computation in drug discovery.计算在药物发现中的多重作用。
Science. 2004 Mar 19;303(5665):1813-8. doi: 10.1126/science.1096361.
9
Predicting undesirable drug interactions with promiscuous proteins in silico.利用计算机模拟预测与多配体蛋白的不良药物相互作用。
Drug Discov Today. 2004 Mar 15;9(6):276-85. doi: 10.1016/S1359-6446(03)03008-3.
10
Drug transport at the blood-brain barrier and the choroid plexus.血脑屏障和脉络丛处的药物转运。
Curr Drug Metab. 2004 Feb;5(1):95-108. doi: 10.2174/1389200043489126.
Zotero 插件