Prodrugs of Neuraminidase Inhibitors for Increased Oral Bioavailability

描述（由申请方提供）：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在制药工业中引起了越来越多的兴趣。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非常有效，IC 50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很差。在TSRL，我们开发了一种氨基酸前药策略，其靶向肠道转运蛋白以增强摄取。然后，吸收的前药的后续活化可以通过前药的靶向酶促水解或前药的化学分解以活化母体化合物而发生。该策略基于对细胞和组织中的转运和活化途径以及前药结构与这些途径的相互作用的分子机理理解。在这个提议中，我们已经开发了两种神经氨酸酶抑制剂的新型氨基酸酰氧基酯前药，并提供了强有力的初步数据，表明这些前药被肠道转运蛋白主动转运，并在原位肠道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，我们可以提高选定的神经氨酸酶抑制剂的口服利用度到一定程度，他们可以开发为口服药物产品。在目前的项目中，我们建议充分表征一系列这些前药的稳定性，组织活化和生物利用度。显示可接受特性的化合物将由犹他州州立大学的NIAID合同机构测试抗H1N1病毒的体内效力。我们的分子机制的前药设计方法具有巨大的潜力，口服有效的神经氨酸酶抑制剂的发展。更广泛地说，这种前体药物策略提供了巨大的潜力和很大的希望，在实现开发可行的口服替代品的最终目标，为更广泛的治疗有效的抗病毒药物。公共卫生相关性：TSRL开发了一种提高抗流感药物口服生物利用度的方法，从而使其适合口服给药。我们建议合成并测试一系列这些化合物作为口服药物的潜力。最终，这种方法可以增加可用于流感的治疗性和预防性治疗的有效抗病毒化合物的数量。

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.