Mechanism of Action of Novel Dual Acting Pyrimidinediones

新型双作用嘧啶二酮类药物的作用机制

• 批准号: 8012622
• 负责人: Robert Walter Buckheit
• 金额: $ 91.95万
• 依托单位: IMQUEST BIOSCIENCES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-03 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8012622
• 关键词: Algorithms; Animal Model; Antiviral Agents; Biochemical; Biological; Biological Availability; Canis familiaris; Cells; Characteristics; Clinical; Clinical Trials; Data; Delavirdine; Development; Dose; Drug Formulations; Drug Kinetics; Drug resistance; Evaluation; Exhibits; Female of child bearing age; Generations; Genetic; Goals; HIV; HIV-1; HIV-2; Highly Active Antiretroviral Therapy; Hour; Human; In Vitro; Investigational New Drug Application; Laboratories; Lead; Liver Microsomes; Metabolism; Microscopic; Microsomes; Multi-Drug Resistance; Mus; Mutation; NNRTI-resistance; Nevirapine; Oral; Pathologic; Patients; Performance; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Plasma; Property; Protease Inhibitor; Protein Binding; RNA-Directed DNA Polymerase; Rattus; Relative (related person); Research; Research Project Grants; Research Proposals; Resistance; Reverse Transcription; Safety; Salvage Therapy; Science; Small Business Innovation Research Grant; Solubility; Sterilization; Structure-Activity Relationship; Testing; Therapeutic; Therapeutic Agents; Time; Toxic effect; Virion; Virus; analog; aqueous; base; comparative; cost; drug resistant virus; efavirenz; expectation; experience; improved; in vitro Assay; inhibitor/antagonist; meetings; next generation; non-nucleoside reverse transcriptase inhibitors; novel; prevent; public health relevance; resistant strain; small molecule; virus culture

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.

说明(由申请人提供)：虽然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，通过额外的开发活动，可以进一步增强生物活性，其中铅分子被定义为我们第一阶段SBIR研究中定义的最活跃的逆转录酶和病毒进入抑制剂。从我们的第一阶段SBIR项目中获得的嘧啶二酮类化合物的构效关系数据表明，第二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。一些具有更大进入和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。根据我们第一阶段提案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，我们打算使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，该药物将根据抗病毒活性、代谢和配方前特征等参数进行定义。在选择我们的第二代嘧啶二酮抑制剂后，我们将利用配方科学来更好地提供有效、稳定和更易溶的嘧啶二酮，以提高生物利用度和药代动力学。我们期望，这项第二阶段的SBIR努力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着的改善。 与公共卫生相关：尽管目前批准的NNRTI(奈韦拉平、地拉韦定、Eefavirenz和etraviine)是高度有效的，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，对育龄妇女易于服药，并具有显著更高的抗药性选择遗传障碍。这项建议的主要目标是从我们第一阶段项目过程中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。根据它们抑制逆转录和病毒进入的相对潜力，这些选定的嘧啶二酮类化合物被优先考虑，它们都是HIV-1的亚纳摩尔到低纳摩尔浓度的抑制剂。对这些分子的详细生物学评估将与优化一种新的铅分子的配方和输送以及使用药物化学来提高选定化合物的溶解度、稳定性和生物利用度相结合。还将利用化合物代谢和蛋白质结合的比较评估来帮助优先考虑和确定具有高度优化的药代动力学特性和对野生型、NNRTI耐药和MDR病毒的可能最高效力的下一代Pryimidinedione临床候选药物。