用于药物发现的单和二化和和异环胺:对其物理化学性质的系统研究
Kostiantyn P Melnykov1,2, Kostiantyn Nazar1,2, Oleh Smyrnov1,2
1Enamine Ltd., Chervonotkatska Street 78, Kyїv, 02094, Ukraine.
Chemistry (Weinheim an der Bergstrasse, Germany)
|June 15, 2023
概括
替代显著影响着亚齐蒂丁,罗利丁和皮佩里丁衍生物的基本性和脂性. 这些化异环表现出高的代谢稳定性,使它们成为药物发现的有价值的基石.
科学领域:
- 药用化学 医学化学
- 有机化学 有机化学
- 药物发现 药物发现 药物发现
背景情况:
- 像pKa和LogP这样的物理化学性质对于药物开发至关重要.
- 的结合是调节这些特性的一个常见策略.
- 和的异环胺是药物化学中的重要支架.
研究的目的:
- 综合研究单和二化亚提丁,罗利丁和皮佩里丁衍生物的物理化学性质.
- 研究替代和形状偏好对这些特性的影响.
- 评估这些新型化异环的代谢稳定性.
主要方法:
- 合成单化和二化亚提丁,皮罗利丁和皮佩里丁衍生物.
- 确定pKa值的方法.
- 计算LogP值的方法.
- 测量内在的微体清除值.
- 整合性分析. 整合性分析.
主要成果:
- 基本性 (pKa) 和脂性 (LogP) 主要受原子数量和相对于质子化部位的位置的影响.
- 符合性偏好显著影响了pKa和LogP值.
- cis-3,5-difluoropiperidine衍生物由于二轴形状 (Janus面孔效应) 出现了不寻常的水友性.
- 大多数化合物表现出高的代谢稳定性,而3,3-difluoroazetidine则是例外.
结论:
- 化和异环胺为药物发现的现有基石提供了有价值的扩展.
- 这些化合物可以通过调节物理化学和代谢性质来合理优化候选药物.
- 该研究强调了在设计化药物分子时考虑构造效应的重要性.
相关概念视频
01:25Basicity of Heterocyclic Aromatic Amines
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Heterocyclic amines, where the N atom is a part of an alicyclic system, are similar in basicity to alkylamines. Interestingly, the heterocyclic amine having a nitrogen atom as part of an aromatic ring has much less basicity than its corresponding alicyclic counterpart. For this reason, as presented in Figure 1, piperidine (pKb = 2.8) is significantly more basic than pyridine (pKb = 8.8).
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01:10Nomenclature of Aryl and Heterocyclic Amines
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The simplest aromatic amine is phenylamine, which contains an –NH2 functionality directly attached to an aromatic ring. The name aniline is designated for this skeleton. As shown in Figure 1, the common names of the functionalized anilines involve prefixes ortho-, meta-, and para- to indicate the substitution position. Different functionalized aniline derivatives also have notable trivial names.
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01:26Physical Properties of Amines
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Amines with low molecular weight are usually gaseous at room temperature, while those with high molecular weight are liquid or solids in nature. Usually, low molecular weight amines have a rotten fish-like smell. Diamines typically have a pungent smell. For instance, cadaverine and putrescine, depicted in Figure 1, are two molecules responsible for decaying tissue.
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01:23Amines to Sulfonamides: The Hinsberg Test
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The Hinsberg test is a method to identify primary, secondary and tertiary amines, named after its pioneer, Oscar Hinsberg. Here, amines are treated with benzenesulfonyl chloride, also known as the Hinsberg reagent, in the presence of an excess of aqueous base, followed by acidification. Based on the nature of the amines, different changes are observed.
Generally, a primary amine reacts with the Hinsberg reagent to produce an N-substituted benzenesulfonamide. The electron-withdrawing...
Generally, a primary amine reacts with the Hinsberg reagent to produce an N-substituted benzenesulfonamide. The electron-withdrawing...
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01:07Preparation of 1° Amines: Hofmann and Curtius Rearrangement Overview
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In the presence of an aqueous base and a halogen, primary amides can lose the carbonyl (as carbon dioxide) and undergo rearrangement to form primary amines. This reaction, called the Hofmann rearrangement, can produce primary amines (aryl and alkyl) in high yields without contamination by secondary and tertiary amines.
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01:07Amines: Introduction
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Amines are organic derivatives of ammonia. They are formed by replacing one or more ammonia protons with alkyl or aryl groups. Depending upon the number of organyl groups bonded to nitrogen, amines are classified as primary, secondary, or tertiary. Primary amines have one organyl group attached to the nitrogen atom, while secondary and tertiary amines have two and three organyl groups attached to the nitrogen atom, respectively.
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