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：
8389628
负责人：
John M Hilfinger
金额：
$ 100万
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 2014-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8389628
关键词：
Acute Affect Amino Acids Animal Model Anti-influenza Agent Antiviral Agents Appearance Back Binding Biological Assay Biological Availability Birds Breathing Cells Cessation of life Characteristics Charge Chemicals Clinical Trials Data Development Disease Outbreaks Dose Drug Industry Drug Kinetics Drug Targeting Ensure Epidemic Esters Family Ferrets GlaxoSmithKline brand of zanamivir Human Hydrolysis In Vitro Influenza Influenza A Virus, H1N1 Subtype Inhibitory Concentration 50 Intestines Investigational Drugs Investigational New Drug Application Lead Life Cycle Stages Mammals Marketing Maximum Tolerated Dose Measures Metabolic Modeling Molecular Mus Neuraminidase Neuraminidase inhibitor Oral Orthomyxoviridae Oseltamivir Parents Pathway interactions Peptides Permeability Pharmaceutical Chemistry Pharmaceutical Preparations Phase Play Population Prodrugs Production Prophylactic treatment RNA Viruses Rattus Reporting Research Resistance Route Safety Scheme Series Sialic Acids Structure Testing Therapeutic Tissues Toxic effect Toxicity Tests Toxicology Vaccination Vaccines Virus Work World Health Organization absorption analog anti-influenza drug base candidate selection carboxylate design drug resistant virus efficacy testing enzyme substrate analog improved in vitro activity in vivo influenzavirus inhibitor/antagonist interest killings nonhuman primate novel pandemic disease pandemic influenza pre-clinical preclinical efficacy preclinical safety prevent public health relevance safety study seasonal influenza swine flu 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 prodrugs of two neuraminidase inhibitors and provide strong supporting data showing that these prodrugs are actively transported by intestinal transporter and are well absorbed. We show that through our approach, we can boost the oral availability of selected neuraminidase inhibitors to an extent that they are effective in animal models of influenza and have high potential to be developed as oral drug products. In the current project, we propose to select a lead neuraminidase inhibitor by in vivo (mouse and ferret) testing of the developed series of compounds against a range of influenza strains, including recent H1N1 isolates, seasonal flu isolates, drug resistant virus and high pathogenic strains of the virus. Our "molecular mechanistic" approach to prodrug design has enormous potential for the development of orally effective neuraminidase inhibitors.

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着关键作用。一类抑制神经氨酸酶作用的抗流感药物因其选择性和效力而引起了制药行业越来越多的兴趣。该抑制剂是酶底物唾液酸的过渡态类似物，在体外和体内研究中非常有效，IC50 值在 nM 范围内。然而，这些药物极性很强，因此口服生物利用度较差。在 TSRL，我们开发了一种氨基酸前药策略，针对肠道转运蛋白以增强吸收。然后，所吸收的前药的后续活化可以通过前药的定向酶促水解或前药的化学分解成活化的母体化合物来发生。该策略基于对细胞和组织中的转运和激活途径以及前药结构与这些途径的相互作用的分子机制理解。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前药，并提供了有力的支持数据，表明这些前药被肠道转运蛋白主动转运并被良好吸收。我们表明，通过我们的方法，我们可以提高选定神经氨酸酶抑制剂的口服利用率，使其在流感动物模型中有效，并且具有开发为口服药物产品的巨大潜力。在当前的项目中，我们建议通过针对一系列流感病毒株（包括最近分离的 H1N1 流感病毒、季节性流感病毒、耐药病毒和高致病性流感病毒）对开发的系列化合物进行体内（小鼠和雪貂）测试，选择一种主要的神经氨酸酶抑制剂。病毒株。我们的前药设计“分子机制”方法对于开发口服有效的神经氨酸酶抑制剂具有巨大的潜力。