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：
8208986
负责人：
John M Hilfinger
金额：
$ 90.41万
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 2013-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8208986
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 Delivery Systems Drug Industry Drug Kinetics 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. 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 anti-influenza 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。在此提案中，我们开发了两种神经氨酸酶抑制剂的新型氨基酸前药，并提供了强大的支持数据，表明这些前药是由肠道转运蛋白积极运输的，并且被充分吸收。我们表明，通过我们的方法，我们可以提高所选神经氨酸酶抑制剂的口服可用性，以便它们在流感的动物模型中有效，并且具有高潜力，可以作为口服药物产生。在当前项目中，我们建议通过体内（小鼠和雪貂）测试一系列针对一系列流感菌株的化合物，包括最近的H1N1分离株，季节性流感分离株，抗药性病毒和该病毒的高致病性菌株。我们的前药设计方法的“分子机理”方法具有开发口服有效的神经氨酸酶抑制剂的巨大潜力。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。我们建议合成和测试一系列这些化合物，以作为口服抗激素剂的潜力。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。