Development of broad spectrum Hepatitis C Virus NS3/4A protease inhibitors

描述(由申请人提供)：这是一项合作建议，旨在开发对丙型肝炎病毒(丙型肝炎病毒)NS3/4A蛋白酶的敏感性降低和活性基因型谱改善的抑制剂。世界上超过3%的人口感染了丙型肝炎病毒。不幸的是，目前最好的治疗方法仍然是 挑战最流行的基因1。由于其在病毒复制中的重要作用，丙型肝炎病毒NS3/4A蛋白水解酶是一个有吸引力的药物靶点。在之前的工作中，我们发现了两种新的支架材料，它们对四种最流行的基因类型显示出抑制活性，其中一种对野生型NS31b的IC50值为~2�M，并且对五种耐药突变株的效力也保持在10倍的范围内。另一种，对较常见的基因型的IC_(50)为~2-20�M，将提供备份打击。我们建议将这些支架开发成一种低分子质量的NS3/4A抑制剂，比现有的治疗方法具有更广泛的光谱活性和更少的副作用。我们将通过三个有针对性的目标来追求这一目标：(1)利用现有HITS的支架扩展来开展更广泛的结构化活动 (2)利用基于结构的设计和合成来进一步改进抑制剂；以及(3)利用代谢稳定性和相关的药代动力学参数，以及丙型肝炎病毒的抗病毒疗效，反复改善抑制剂设计的治疗特征。有了这些目标，我们希望达到里程碑式的成功标准，其中包括：将抑制剂酶促IC50降至�10纳米；获得抗病毒EC50�100纳米(复制子试验)；与其他非靶标酶相比，保持对NS3/4A良好的酶选择性；小鼠微粒体稳定性，T1/2&GT；30分钟；良好口服生物利用度的可能性；以及最低的细胞毒性，选择性指数SI�100。

DESCRIPTION (provided by applicant): This is a collaborative proposal to develop inhibitors with reduced susceptibility to resistance and improved genotype spectrum of activity against the NS3/4A protease of the Hepatitis C virus (HCV). Over three percent of the world's population is infected with the hepatitis C virus (HCV). Unfortunately, the current best treatment is still quite challenging against the most prevalent genotype 1. The HCV NS3/4A protease is an attractive drug target due to its essential role in viral replication. In prior work, we discovered two novel scaffolds that show inhibitory activity against four of the most prevalent genotypes, one of which shows an IC50 value of ~2 �M against wild type NS3 genotype 1b, and also maintained its potency within a 10-fold range against five drug-resistant mutants. Another, with an IC50 of ~2-20 �M against the more common genotypes will provide a backup hit. We propose to develop these scaffolds into a low molecular weight NS3/4A inhibitor with broader spectrum activity and fewer side effects than current therapeutics. We will pursue this goal through three targeted aims to (1) utilize scaffold expansion of current hits to develop more extensive Structure Activity Relationships (SARs) to increase potency by at least an order of magnitude; (2) use structure-based design and synthesis to further improve inhibitors; and (3) utilize metabolic stability and related pharmacokinetic parameters, along with HCV antiviral efficacy to iteratively improve inhibitor design therapeutic characteristics. With these Aims, we expect to attain Milestone criteria for success that include: reducing the inhibitor enzymatic IC50 to � 10 nM; obtaining antiviral EC50 � 100 nM (replicon assay); retaining good enzymatic selectivity for NS3/4A vs. other off-target enzymes; mouse microsomal stability, t1/2 > 30 min; potential for good oral bioavailability; and minimal cytotoxicity, with a selectivity index, SI � 100.