Mechanism of Action of Novel Dual Acting Pyrimidinediones

描述（由申请方提供）：尽管IQP-0410具有良好的药代动力学、安全药理学和毒性特征，但我们认为，通过对我们I期SBIR研究中定义为最具活性的逆转录酶和病毒进入抑制剂的先导分子进行额外的开发活动，可以进一步增强生物活性。从我们的I期SBIR项目中获得的嘧啶二酮的结构-活性关系数据表明，第二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。已经确定了许多具有更大的进入和RT抑制潜力和稳定性的初始先导化合物用于进一步开发。根据我们I期研究的结果以及我们目前临床候选药物嘧啶二酮IQP-0410的开发经验，我们打算采用传统药物化学来改善新选择的嘧啶二酮的溶解度和稳定性，这将根据包括抗病毒活性、代谢和预配制特征在内的参数进行定义。在选择我们的第二代嘧啶二酮抑制剂后，我们将采用配方科学更好地提供强效，稳定和更可溶的嘧啶二酮，以提高生物利用度和药代动力学。我们期望这一II期SBIR工作将在我们的下一代临床候选药物的治疗效用和效力方面产生显著改善。 公共卫生相关性：虽然目前批准的非核苷类逆转录酶抑制剂（奈韦拉平，地拉韦啶，依法韦仑和依曲韦林）是非常有效的，治疗效用的显着改善仍然需要。必须开发新一代NNRTI，其将允许每天给药一次，表现出显著降低的毒性，适合于育龄妇女给药，并具有显著更高的耐药选择遗传屏障。本提案的主要目标是从I期项目期间定义的高活性先导化合物中定义并开始IND指导的第二代嘧啶二酮临床治疗候选药物的开发。这些选择的先导嘧啶二酮已基于其抑制逆转录和病毒进入的相对潜力而被优先考虑，并且都是亚纳摩尔至低纳摩尔浓度的HIV-1抑制剂。这些分子的详细生物学评价将与优化新先导分子的制剂和递送以及使用药物化学来改善所选化合物的溶解度、稳定性和生物利用度的努力相结合。还将利用化合物代谢和蛋白结合的比较评价来帮助优先考虑和确定下一代嘧啶二酮临床候选药物，该药物具有高度优化的药代动力学特性和对野生型、NNRTI耐药和MDR病毒的最高可能效力。

DESCRIPTION (provided by applicant): Although IQP-0410 possesses a favorable pharmacokinetic, safety pharmacology and toxicity profile, we believe that additional enhancement of biological activity is possible through additional development activities with lead molecules defined as the most active reverse transcriptase and virus entry inhibitors defined in our Phase I SBIR studies. Structure-activity relationship data obtained with the pyrimidinediones from our Phase I SBIR project indicates that a second generation pyrimidinedione may also be expected to meet and potentially exceed these necessary properties for a next generation NNRTI. A number of initial lead compounds with greater entry and RT inhibitory potential and stability have been identified for further development. Based on the results of our Phase I proposal as well as our experience with the development of our current clinical candidate pyrimidinedione IQP-0410, we intend to employ traditional medicinal chemistry to improve the solubility and stability of a new select pyrimidinedione, which will be defined according to parameters including antiviral activity, metabolism, and preformulation characteristics. Upon selection of our second generation pyrimidinedione inhibitor, we will employ formulation science to better deliver the potent, stable and more soluble pyrimidinedione to enhance bioavailability and pharmacokinetics. It is our expectation that this Phase II SBIR effort will yield a significant improvement in the therapeutic utility and potency of our next generation clinical candidate. PUBLIC HEALTH RELEVANCE: Although the currently approved NNRTIs (nevirapine, delavirdine, efavirenz and etravirine) 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 women of child bearing age, and possess a significantly higher genetic barrier to resistance selection. The primary goal of this proposal is to define and begin IND-directed development of a second generation pyrimidinedione clinical therapeutic candidate from among the highly active lead compounds defined during the course of our Phase I project. These selected lead pyrimidinediones have been prioritized based on their relative potential to inhibit both reverse transcription and virus entry and all are sub-nanomolar to low nanomolar concentration inhibitors of HIV-1. Detailed biological evaluation of these molecules will be combined with efforts to optimize the formulation and delivery of a new lead molecule, as well as the use of medicinal chemistry to improve the solubility, stability, and bioavailability of the selected compound. Comparative evaluation of compound metabolism and protein binding will also be utilized to help prioritize and define the next generation pryimidinedione clinical candidate possessing highly optimized pharmacokinetic properties and the highest possible potency against wild type, NNRTI-resistant and MDR viruses.