Mechanism of Action of Novel Dual Acting Pyrimidinediones

描述（由申请人提供）：尽管IQP-0410具有良好的药代动力学、安全性药理学和毒性特征，但我们相信，通过在我们的I期SBIR研究中定义的最活跃的逆转录酶和病毒进入抑制剂铅分子的额外开发活动，可以进一步增强生物活性。从我们一期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。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已被确定用于进一步开发。基于I期申请的结果，以及我们目前临床候选嘧啶二酮IQP-0410的开发经验，我们打算采用传统药物化学来提高新选择的嘧啶二酮的溶解度和稳定性，这将根据抗病毒活性、代谢和预制剂特性等参数来定义。在选择第二代嘧啶二酮抑制剂后，我们将利用配方科学更好地提供强效、稳定、易溶的嘧啶二酮，以提高生物利用度和药代动力学。我们期望这项II期SBIR的努力将显著提高我们下一代临床候选药物的治疗效用和效力。

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.