基于piperazinotriazole的NK3R抗体:口服活性化合物的合理设计,合成和鉴定
Fangxia Zou1, Yashi Zhou1, Hui Wang2
1School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, 264005, PR China.
European journal of medicinal chemistry
|February 1, 2026
概括
一种新的候选药物,23i(R),通过有效地阻断神经基因-3受体 (NK3R),显示出作为治疗更年期热的非荷尔蒙治疗的希望. 这种下一代NK3R抗剂在临床前研究中表现出卓越的特性.
科学领域:
- 药理学 药理学是指药理学的学科.
- 药用化学 医学化学
- 内分泌学 在内分泌学.
背景情况:
- 更年期热是常见的症状,非荷尔蒙治疗选择有限.
- 神经基因-3受体 (NK3R) 是一个有效的点管理热的目标.
- 费索利内坦目前是唯一批准的NK3R抗剂,突出显示了对替代疗法的需要.
研究的目的:
- 设计和合成新的伊米达比佩拉衍生物作为潜在的NK3R抗剂.
- 评估这些新型化合物的药理性质和临床前疗效.
- 为了确定一个有前途的临床候选人治疗更年期热.
主要方法:
- 合成伊米达比佩拉衍生物.
- 在体外测试NK3R抑制和标结合.
- 评估膜透性和口服生物可用性.
- 在卵巢切除的老鼠模型中进行体内研究,以评估疗效和药理动力学.
主要成果:
- 化合物23i(R表现出强大的NK3R抑制 (IC50 = 65.42 ± 6.54 nM) 和强大的对象结合 (IC50 = 53.61 ± 3.67 nM).
- 23i(R) 显示出优异的膜透性 (Papp A-B = 27.3 × 10^-6 cm/s) 和显著的口服生物利用性 (165%).
- 在体内,23i(R) 在卵巢切除的老鼠中有效抑制了黄素激素水平,具有有利的药理动力学和耐受性.
结论:
- 23i(R) 是一种有力的口服生物可用NK3R抗剂,具有前临床有效性.
- 该化合物表现出有利的药理动力学和耐受性概况.
- 23i(R) 是新一代非激素治疗更年期热的有希望的临床候选者.
相关概念视频
01:18Anticoagulant Drugs: Vitamin K Antagonists and Direct Oral Anticoagulants
2.4K
Oral anticoagulants are vital tools in preventing and treating blood clotting disorders. This diverse class of medications can be categorized as vitamin K antagonists, exemplified by warfarin, and direct thrombin inhibitors (DTIs), such as dabigatran, as well as factor Xa inhibitors, including rivaroxaban.
Warfarin, a prominent vitamin K antagonist family member, exerts its effect by inhibiting the enzyme VKORC1 (vitamin K epoxide reductase complex 1). By hindering this enzyme, warfarin...
Warfarin, a prominent vitamin K antagonist family member, exerts its effect by inhibiting the enzyme VKORC1 (vitamin K epoxide reductase complex 1). By hindering this enzyme, warfarin...
2.4K
01:29Cholinergic Antagonists: Chemistry and Structure-Activity Relationship
2.8K
Cholinergic antagonists bind to cholinergic receptors and limit the effects of acetylcholine and other cholinergic agonists. Based on the specific cholinergic receptor affinity, these antagonists are classified as muscarinic or nicotinic. Anticholinergics interrupt parasympathetic innervations while sympathetic innervations remain uninterrupted. Muscarinic antagonists are also called 'muscarinic antagonists', 'antimuscarinics', or 'parasympatholytics'. Nicotinic...
2.8K
01:29Rationalizing Substitutions
59
Integrals involving non-rational functions are often difficult to evaluate using standard techniques, especially when radicals appear in the integrand. Rationalizing substitution provides a systematic method for simplifying such integrals by converting them into rational forms that are easier to handle.Consider a rod whose linear mass density depends on a constant linear density, a characteristic length, and the distance from the left end of the rod. Determining the total mass requires...
59
01:28Rational Expressions
392
Rational expressions are algebraic fractions in which both the numerator and the denominator are polynomials. These expressions follow the arithmetic rules of numerical fractions but require extra care due to the presence of variables. A fundamental part of working with rational expressions is identifying values that make the expression undefined, typically those that result in division by zero or undefined radicals.Determining the DomainThe domain of a rational expression includes all real...
392
03:02Organic Compounds
57.4K
All living things are formed mostly of carbon compounds called organic compounds. The category of organic compounds includes both natural and synthetic compounds that contain carbon. Although a single, precise definition has yet to be identified by the chemistry community, most agree that a defining trait of organic molecules is the presence of carbon as the principal element, bonded to hydrogen and other carbon atoms. However, some carbon-containing compounds such as carbonates, cyanides, and...
57.4K
02:17Synthesis and Decomposition Reactions
38.2K
Synthesis and decomposition are two types of redox reactions. Synthesis means to make something, whereas decomposition means to break something. The reactions are accompanied by chemical and energy changes.
38.2K