口服因子D抑制剂治疗补体介导性疾病的临床研究

IF 3.5 3区 医学 Q2 CHEMISTRY, MULTIDISCIPLINARY
Venkat R Gadhachanda, Jason A Wiles, Steven D Podos, David Boyer, Jane Thanassi, Dhara Patel, Yongsen Zhao, Lijuan Wang, Mingjun Huang
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引用次数: 0

摘要

目的:本研究的目的是发现补体因子D (FD)的小分子抑制剂,补体因子D是激活补体替代途径(AP)的必需蛋白酶,具有临床研究补体介导疾病如突发性夜间血红蛋白尿(PNH)的特征。方法:合成化合物并进行体外效价、选择性和代谢稳定性测试。优化后的化合物进一步进行了一系列体外一级和二级药理学试验,包括对FD的抑制作用,不同的补体途径和疾病模型,以及动物药代动力学和药效学评估。结果:经过多轮优化,达尼可泮和后来的蠕虫泮成为临床研究的候选药物。两种化合物均表现出对FD和AP的有效和选择性抑制作用,适合口服给药的药代动力学特征,以及对PNH体外疾病模型的疗效。除了体外效力增强外,与达尼可潘相比,维美可潘在动物研究中表现出更低的清除率和更高的生物利用度。结论:达尼可潘和蠕虫潘的临床前评价为开展补体介导疾病的临床研究提供了依据。最近,danicopan被批准作为C5抑制剂ravulizumab或eculizumab的附加治疗,用于治疗PNH患者的血管外溶血。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
First-in-Class Clinically Investigated Oral Factor D Inhibitors for the Treatment of Complement-Mediated Diseases.

Objective: The global of the study was to discover small molecular inhibitors of complement factor D (FD), an essential protease for activation of the alternative pathway (AP) of complement, that possess the characteristics for clinical investigation in complement-mediated diseases such as paroxysmal nocturnal hemoglobinuria (PNH).

Methods: Compounds were synthesized and tested in vitro for potency, selectivity, and metabolic stability. The optimized compounds were subjected further to a panel of in vitro tests for primary and secondary pharmacology including inhibitory effects on FD, different complement pathways and disease models, as well as to pharmacokinetic and pharmacodynamic evaluations in animals.

Results: Following multiple rounds of optimization, danicopan and later vermicopan were chosen as candidates for clinical investigation. Both compounds demonstrated potent and selective inhibitory effects on FD and AP, suitable pharmacokinetic characteristics for oral dosing, and efficacy in PNH in vitro disease models. In addition to enhanced in vitro potency, vemircopan exhibited lower clearance and higher bioavailability in animal studies compared with danicopan.

Conclusion: Preclinical evaluations of danicopan and vermicopan provided rationales to conduct clinical studies in complement-mediated diseases. Recently, danicopan was approved as an add-on therapy to the C5 inhibitors ravulizumab or eculizumab for the treatment of extravascular hemolysis in patients with PNH.

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来源期刊
Pharmaceutical Research
Pharmaceutical Research 医学-化学综合
CiteScore
6.60
自引率
5.40%
发文量
276
审稿时长
3.4 months
期刊介绍: Pharmaceutical Research, an official journal of the American Association of Pharmaceutical Scientists, is committed to publishing novel research that is mechanism-based, hypothesis-driven and addresses significant issues in drug discovery, development and regulation. Current areas of interest include, but are not limited to: -(pre)formulation engineering and processing- computational biopharmaceutics- drug delivery and targeting- molecular biopharmaceutics and drug disposition (including cellular and molecular pharmacology)- pharmacokinetics, pharmacodynamics and pharmacogenetics. Research may involve nonclinical and clinical studies, and utilize both in vitro and in vivo approaches. Studies on small drug molecules, pharmaceutical solid materials (including biomaterials, polymers and nanoparticles) biotechnology products (including genes, peptides, proteins and vaccines), and genetically engineered cells are welcome.
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