Development of Pyrimidinedione NNRTIs With a High Genetic Barrier to Resistance

描述（由申请人提供）：尽管目前批准的nnrti（奈韦拉平、德拉韦林、依非韦伦、依特里维林）是非常有效的，但仍需要在治疗效用方面进行重大改进。必须开发新一代的NNRTIS，它将允许每天一次给药，表现出明显降低的毒性，适合育龄妇女给药，并具有明显更高的抗性选择遗传屏障。由Tibotec （Etrivirine）和Idenix （IDX-899）开发的NNRTIs似乎具有许多这些有希望的治疗特性，这些化合物目前已被批准使用或进入3期人体临床试验。得到的结构-活性关系数据表明，下一代嘧啶二酮也有望满足并可能超过下一代NNRTI的这些必要性质，并且已经确定了各种初始先导化合物供进一步开发。在给药后24小时血浆血药浓度超过所需EC95浓度20倍的情况下，嘧啶二酮类药物可以每天给药一次。此外，ImQuest已经启动了优化iqc -0410的配方和给药的研究，初步结果表明该谷底药物浓度将进一步提高。嘧啶二酮已在小鼠、大鼠和狗身上以高达2000mg /kg/天的浓度给药，没有任何明显的或显微镜下的毒性病理迹象，这表明这些化合物对人类可能是非常安全的，因此在临床上可能对育龄妇女有用。最重要的是，基于对常见问题nnrti耐药和MDR病毒的初步抗病毒数据以及确定的嘧啶二酮的第二种作用机制，嘧啶二酮有望具有极高的耐药遗传屏障。虽然我们目前的先导化合物IQP-0410似乎对这些耐药菌株具有良好的活性，但其他类似物已被发现对耐药菌株具有更强的效力。在嘧啶二酮系列分子中，产生nnrti抗性突变的明显初始极限约为100至200倍，因为在该浓度水平下，nnrti抗性病毒的复制通过进入抑制机制受到抑制。因此，为了实现对嘧啶二酮的高水平抗性，我们已经证明，在逆转录酶中必须积累多个突变，并且突变必须出现在gp120和gp41中，从而实现抗性选择的高遗传屏障。公共卫生相关性：本提案的总体目标是确定新的先导治疗候选化合物，对nnrti耐药和MDR病毒具有最高的效力。通过我们的SAR评估，已经发现了对这些病毒具有更强效力的先导化合物，这些化合物将使用标准药物化学进一步修饰，以提高它们对耐药病毒的活性，提高它们的溶解度，并提高它们的整体口服生物利用度。通过鉴定具有更大分子柔韧性的化合物，使其能够在NNRTI产生抗性突变的情况下更好地与疏水性NNRTI结合口袋结合，以及通过鉴定增强化合物抑制病毒进入能力的修饰，可以增强嘧啶二酮的效力。改善溶解度和生物利用度的修饰也有望增强我们的给药方案，以进一步提高化合物的疗效。

DESCRIPTION (provided by applicant): Although the currently approved NNRTIs (nevirapine, delavirdine, efavirenz, etrivirine) are highly potent, significant improvements in therapeutic utility are still required. A new generation of NNRTIS must be developed which will allow once per day dosing, exhibit significantly reduced toxicity, be amenable to dosing in woman of child bearing age, and possess a significantly higher genetic barrier to resistance selection. NNRTIs being developed by Tibotec (Etrivirine) and Idenix (IDX-899) appear to possess many of these promising therapeutic properties and these compounds are currently approved for use or entering Phase 3 human clinical trials. Structure-activity relationship data obtained with the pyrimidinediones indicates that a next generation pyrimidinedione may also be expected to meet and potentially exceed these necessary properties for a next generation NNRTI and a variety of initial lead compounds have been identified for further development. The pyrimidinediones are amenable to once per day dosing with plasma blood concentrations in excess of 20-times the required EC95 concentration achieved at 24 hours post-dosing. Additionally, ImQuest has initiated studies to optimize the formulation and delivery of IQP-0410 and preliminary results suggest further enhancement to this trough drug concentration. The pyrimidinediones have been dosed in mice, rats and dogs at concentrations of up to 2000 mg/kg/day without any overt or microscopic pathologic signs of toxicity suggesting that the compounds will likely be very safe in humans, and thus may be clinically useful in woman of child bearing age. Most importantly, the pyrimidinediones would be expected to possess an extremely high genetic barrier to resistance based on preliminary antiviral data against common problematic NNRTI-resistant and MDR viruses as well as the defined second mechanism of action of the pyrimidinediones. Though our current lead compound IQP-0410 appears to have favorable activity against these drug resistant strains, additional analogs have been identified with much more potency against drug resistant strains. Among the pyrimidinedione series of molecules, the apparent initial limit to resistance with NNRTI-resistance engendering mutations is approximately 100- to 200-fold since at that concentration level, the replication of NNRTI-resistant virus is suppressed through the entry inhibitory mechanism. Thus, in order to achieve high level resistance to the pyrimidinediones we have shown that multiple mutations must accumulate in the reverse transcriptase AND mutations must appear in both gp120 and gp41, enabling a high genetic barrier to resistance selection. PUBLIC HEALTH RELEVANCE: The overall goal of this proposal is to define new lead therapeutic candidate compounds with the highest possible potency against NNRTI-resistant and MDR viruses. Lead compounds with greater potency against these viruses have been identified through our SAR evaluations, and these compounds will be further modified using standard medicinal chemistry to improve their activity against resistant viruses, to improve their solubility, and to improve their overall oral bioavailability. Enhanced potency of the pyrimidinediones may be achieved by identifying compounds with greater molecular flexibility allowing them to better bind to the hydrophobic NNRTI-binding pocket in the presence of NNRTI resistance-engendering mutations, as well as by identifying modifications which enhance the ability of the compounds to inhibit virus entry. Modifications which improve solubility and bioavailability are also expected to allow enhancements to our dosing regimen to drive further improvements in compound efficacy.