Prodrugs of Neuraminidase Inhibitors for Increased Oral Bioavailability

用于增加口服生物利用度的神经氨酸酶抑制剂前药

基本信息

批准号：
7611581
负责人：
John M Hilfinger
金额：
$ 18.56万
依托单位：
TSRL, INC.
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-20 至 2010-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7611581
关键词：
Amino Acids Animal Model Antiviral Agents Biological Availability Cell surface Cells Characteristics Charge Chemicals Contracts Data Development Drug Delivery Systems Drug Industry Drug Kinetics Enzyme Inhibitor Drugs Enzyme Inhibitors Esters Goals Human Hydrolysis In Situ In Vitro Industry Influenza Influenza A Virus, H1N1 Subtype Inhibitory Concentration 50 Intestines Life Cycle Stages Membrane Modeling Molecular Mus National Institute of Allergy and Infectious Disease Nature Neuraminidase Neuraminidase inhibitor Oral Oseltamivir Parents Pathway interactions Permeability Pharmaceutical Preparations Plasma Play Prodrugs Prophylactic treatment Role Series Sialic Acids Simulate Structure Testing Therapeutic Tissues Universities Utah Virion Virus Work absorption analog anti-influenza anti-influenza drug base carboxylate design efficacy testing enzyme substrate analog improved in vivo influenzavirus inhibitor/antagonist interest novel public health relevance stability testing uptake zanamivir

项目摘要

DESCRIPTION (provided by applicant): Virally-encoded neuraminidase plays a key role in the life-cycle of the influenza virus. A class of anti-influenza drugs that inhibits the action of neuraminidase has garnered increasing interest in the pharmaceutical industry due to their selectivity and potency. The inhibitors are transition state analogs of the enzyme substrate, sialic acid, and are highly efficacious in in vitro and in vivo studies, with IC50 values in the nM range. However these drugs are very polar and consequently have poor oral bioavailability. At TSRL, we have a developed an amino acid prodrug strategy that targets intestinal transporters for enhanced uptake. Subsequent activation of the absorbed prodrug can then occur either through targeted enzymatic hydrolysis of the prodrug or chemical breakdown of the prodrug to the activate parent compound. This strategy is based on a molecular mechanistic understanding of the transport and activation pathways in cells and tissues and the interaction of prodrug structures with these pathways. In this proposal, we have developed novel amino acid acyloxy ester prodrugs of two neuraminidase inhibitors and provide strong preliminary data showing that these prodrugs are actively transported by intestinal transporter and have good intestinal permeability in an in situ intestinal permeability model. We hypothesize that through this prodrug approach, we can boost the oral availability of selected neuraminidase inhibitors to an extent that they can be developed as oral drug products. In the current project, we propose to fully characterize a series of these prodrugs with regard to their stability, tissue activation, and bioavailability. Compounds showing acceptable characteristics will be tested for in vivo efficacy against the H1N1 virus by the NIAID contract facility at Utah State University. Our molecular mechanistic approach to prodrug design has enormous potential for the development of orally effective neuraminidase inhibitors. More broadly, this prodrug strategy offers great potential and much promise in reaching the ultimate goal of developing viable oral alternatives for a wider range of therapeutically potent antiviral agents. PUBLIC HEALTH RELEVANCE: TSRL has developed an approach to improve the oral bioavailability of anti-influenza drugs, thus making them suitable for oral delivery. We propose to synthesize and test a series of these compounds for their potential as oral agents. Ultimately, this approach may increase the number of potent anti-virus compounds that are available for therapeutic and prophylactic treatment of influenza.

描述（由申请人提供）：病毒编码的神经氨酸酶在流感病毒的生命周期中起关键作用。一类抑制神经氨酸酶作用的抗激素药物由于其选择性和效力而引起了对制药行业的兴趣。抑制剂是酶酸酯，唾液酸的过渡状态类似物，在体外和体内研究中具有高效的症状，IC50值在NM范围内。但是，这些药物非常极性，因此口服生物利用度较差。在TSRL，我们有一个开发的氨基酸前药策略，该策略靶向肠道转运蛋白以增强摄取。然后，可以通过靶向酶促水解对前药的靶向酶学水解进行随后的激活，或者可以使前药的化学分解或化学分解。该策略基于对细胞和组织中传输和激活途径的分子机械理解以及前药结构与这些途径的相互作用。在该提案中，我们开发了两种神经氨酸酶抑制剂的新型氨基酸氧化酯前药，并提供了强有力的初步数据，表明这些前药是由肠道转运蛋白积极运输的，并且具有良好的肠道渗透性，并且在原位肠内通透性模型中具有良好的肠道通透性。我们假设通过这种前药方法，我们可以提高所选神经氨酸酶抑制剂的口服可用性，以至于它们可以作为口服药品开发。在当前的项目中，我们建议完全表征一系列这些前药，这些前药在它们的稳定性，组织激活和生物利用度方面。犹他州立大学的NIAID合同设施将测试显示出可接受特征的化合物对H1N1病毒的体内功效。我们的前药设计分子机械方法具有开发口服有效的神经氨酸酶抑制剂的巨大潜力。更广泛地说，这种前药策略在实现最终目标的最终目标方面为更广泛的治疗性抗病毒剂提供了巨大的最终目标。公共卫生相关性：TSRL已开发出一种改善抗激素药物的口服生物利用度的方法，从而使其适合口服分娩。我们建议合成并测试一系列这些化合物，以发挥其作为口服剂的潜力。最终，这种方法可能会增加用于流感的治疗和预防性治疗的有效抗病毒化合物的数量。