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、地拉韦定、依那韦林、依曲韦林)非常有效，但仍需在治疗效用方面进行重大改进。必须开发新一代NNRTI，它将允许每天给药一次，显示出显著降低的毒性，对育龄妇女易于给药，并具有显著更高的抗性选择遗传障碍。Tibotec(依曲韦林)和Idenix(IDX-899)正在开发的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用于或进入第三阶段人体临床试验。与嘧啶二酮类化合物的构效关系数据表明，下一代嘧啶二酮类化合物也有望达到并可能超过下一代NNRTI的这些必要性质，各种初始先导化合物已被确定用于进一步开发。在血浆血药浓度超过24小时所需EC95浓度的20倍的情况下，嘧啶二酮类药物每天给药一次。此外，ImQuest已经启动了优化IQP-0410配方和输送的研究，初步结果表明，这一低谷药物浓度将进一步提高。这些嘧啶二酮类化合物在小鼠、大鼠和狗身上的剂量高达2000毫克/公斤/天，没有任何明显或微观的毒性病理迹象，这表明这些化合物可能对人类非常安全，因此可能对育龄妇女有临床用途。最重要的是，根据对常见问题NNRTI耐药和多药耐药病毒的初步抗病毒数据，以及已确定的嘧啶二酮类第二作用机制，预计嘧啶二酮类化合物将具有极高的抗药性遗传屏障。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耐药突变的表观初始抗药性极限约为100-200倍，因为在该浓度水平，NNRTI耐药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类药物的高水平抗性，我们已经证明，逆转录酶中必须积累多个突变，并且gp120和gp41中都必须出现突变，这使得抗性选择具有很高的遗传障碍。与公共卫生相关：这项提议的总体目标是定义新的具有最高效力的新的治疗候选化合物，以对抗NNRTI耐药和MDR病毒。通过我们的SAR评估，已经确定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的药物化学进行进一步的修饰，以提高它们对耐药病毒的活性，改善它们的溶解性，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灵活性的化合物，使它们在存在NNRTI耐药突变的情况下更好地与疏水NNRTI结合口袋结合，以及通过鉴定增强化合物抑制病毒进入的能力的修饰，可以实现嘧啶二酮类化合物的效力增强。改善溶解性和生物利用度的修饰预计也将允许改进我们的给药方案，以推动化合物疗效的进一步改善。

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.