非古典Zwitterions作为一个设计原则,以减少脂性,而不会影响透性
Henrik Möbitz1, Birger Dittrich1, Stephane Rodde1
1Novartis BioMedical Research, 4002 Basel, Switzerland.
Journal of medicinal chemistry
|May 15, 2024
概括
双子是具有正负电荷的分子,即使具有相似的酸和强度,也可以形成. 这些非经典的zwitterions为药物化学应用提供了改善的药物透性和脂性.
科学领域:
- 药用化学 医学化学
- 物理化学 物理化学
- 药物发现 药物发现 药物发现
背景情况:
- 生物活性分子的电离显著影响ADME相关的特性,如溶解性,脂性和透性.
- 拥有酸性和基本性两种组的叶植物被归类为普通叶植物或zwitterions.
- 一种普遍的观点表明,只有当酸性pKa大大低于基本的pKa时,zwitterion才会形成.
研究的目的:
- 为了研究生物活性分子中zwitterionic行为发生的条件.
- 挑战zwitterion形成的既定标准.
- 为了探索非经典的zwitterions的物理化学特性和药用化学含义.
主要方法:
- 测量和计算pKa值的对应性分析.
- 对log P (脂性) 测量结果的评估.
- 分子结构的表征,包括芳香结合和分子内键.
主要成果:
- 在几种药物和天然产品中观察到zwitterionic行为,尽管dpKa低或负 (酸性和基本性pKa之间的差异).
- 这些非经典的特具有较弱的酸性和基本的pKa值和扩展的芳香系统,通常由分子内键形成的伪环.
- 非古典的zwiterions表现出极好的透性,与典型的zwiterions形成鲜明对比.
结论:
- 兹维特里昂的形成并没有受到ΔpKa标准的严格限制.
- 具有特定结构特征的非古典型,在药物化学中具有宝贵的设计策略.
- 低脂性和高透性的组合使得非经典的兹维特里昂在开发新疗法方面具有吸引力.
更多相关视频
相关概念视频
01:21Factors Affecting Dissolution: Drug pKa, Lipophilicity and GI pH
1.3K
Drug absorption within the gastrointestinal (GI) tract is a complex process influenced by several critical factors, including the site pH, the drug's dissociation constant (pKa), and the drug's lipophilicity. The GI tract exhibits a pH gradient, with an acidic environment in the stomach and a more alkaline environment in the small intestine. This pH variation directly affects the ionization state of drugs.
A drug's pKa and the pH of the gastrointestinal (GI) tract play crucial roles...
A drug's pKa and the pH of the gastrointestinal (GI) tract play crucial roles...
1.3K
01:17Pore Transport and Ion-Pair Transport
431
Pore transport and ion-pair formation are critical mechanisms for the absorption and distribution of drugs in the body.
Pore transport, also known as convective transport, is a process where small molecules like urea, water, and sugars rapidly cross cell membranes as though there were channels or pores in the membrane. Although direct microscopic evidence is limited but the concept of pores or channels is widely accepted based on physiological evidence. Despite the lack of direct...
Pore transport, also known as convective transport, is a process where small molecules like urea, water, and sugars rapidly cross cell membranes as though there were channels or pores in the membrane. Although direct microscopic evidence is limited but the concept of pores or channels is widely accepted based on physiological evidence. Despite the lack of direct...
431
01:23Drug Absorption Mechanism: Passive Membrane Transport
3.8K
Passive transport is a method of drug absorption where small, lipid-soluble drugs can move across the cell membrane. This movement happens along the concentration gradient, which is a natural flow from higher to lower concentration areas. The speed at which the drug moves is directly related to its lipid–water partition coefficient. This means that the more a drug dissolves in lipids, the faster it diffuses or spreads throughout the body. It is important to note that most drugs are either...
3.8K
01:20Factors Affecting Dissolution: Drug Permeability, Stability and Stereochemistry
200
Orally administered drugs primarily enter the systemic circulation via passive diffusion through the intestinal membranes. The drug's absorption is influenced by drug stability in the gastrointestinal GI tract, membrane permeability, the surface area available for absorption, luminal drug concentration, and residence time in the lumen. Drug permeability can be enhanced by adjusting the lipophilicity, polarity, or molecular size of the drug, promoting its passive transport across intestinal...
200
01:35Asymmetric Lipid Bilayer
7.2K
Biological membranes show uneven distribution of different types of lipids in the inner and outer layers, resulting in transverse asymmetric membranes. The treatment of the erythrocyte membrane with the enzyme phospholipase confirmed the asymmetric nature of the lipid bilayer. The enzyme hydrolyzes lipids into fatty acids and hydrophilic groups. The phospholipase acts only on the outer layer of the membrane, while the inner layer remains intact. The phospholipase treatment resulted in 80%...
7.2K
01:23Membrane Fluidity
152.1K
Cell membranes are composed of phospholipids, proteins, and carbohydrates loosely attached to one another through chemical interactions. Molecules are generally able to move about in the plane of the membrane, giving the membrane its flexible nature called fluidity. Two other features of the membrane contribute to membrane fluidity: the chemical structure of the phospholipids and the presence of cholesterol in the membrane.
152.1K