Prodrugs of Neuraminidase Inhibitors for Increased Oral Bioavailability

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流感药物由于其选择性和效力而引起了制药行业越来越多的兴趣。这些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都非常有效，IC50值在nM范围内。然而，这些药物是极极性的，因此口服生物利用度很差。在TSRL，我们开发了一种针对肠道转运蛋白的氨基酸前药策略，以增强摄取。吸收的前药的后续活化可以通过前药的靶向酶解或前药的化学分解到活化的母体化合物来发生。这一策略是基于对细胞和组织中转运和激活途径的分子机制理解，以及前药结构与这些途径的相互作用。在本研究中，我们开发了两种神经氨酸酶抑制剂的新型氨基酸前药，并提供了强有力的支持数据，表明这些前药被肠道转运蛋白积极转运并且吸收良好。我们表明，通过我们的方法，我们可以在一定程度上提高选定的神经氨酸酶抑制剂的口服有效性，使它们在流感动物模型中有效，并且具有很大的潜力开发为口服药物产品。在目前的项目中，我们建议通过体内（小鼠和雪貂）测试开发的一系列化合物来选择一种先导神经氨酸酶抑制剂，以对抗一系列流感毒株，包括最近的H1N1分离株，季节性流感分离株，耐药病毒和高致病性病毒株。我们的“分子机制”前药设计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。

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.