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: 8079483
• 负责人: Robert Walter Buckheit
• 金额: $ 86.17万
• 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/8079483
• 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.

描述（由申请人提供）：尽管 IQP-0410 具有良好的药代动力学、安全药理学和毒性特征，但我们相信，通过使用我们 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。从我们的第一阶段 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 的这些必要特性。一些具有更大的进入和 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。根据我们一期提案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，该新选择的嘧啶二酮将根据抗病毒活性、代谢和预制剂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，我们将采用配方科学来更好地提供有效、稳定和更易溶解的嘧啶二酮，以提高生物利用度和药代动力学。我们期望这项 II 期 SBIR 工作将显着改善我们下一代临床候选药物的治疗效用和效力。 公共健康相关性：尽管目前批准的 NNRTI（奈韦拉平、地拉韦啶、依非韦伦和依曲韦林）非常有效，但仍需要显着提高治疗效用。必须开发新一代 NNRTI，使其每天给药一次，毒性显着降低，适合育龄妇女给药，并且具有显着更高的抗性选择遗传障碍。该提案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第二代嘧啶二酮临床治疗候选药物的 IND 指导开发。这些选定的先导嘧啶二酮类药物已根据其抑制逆转录和病毒进入的相对潜力进行了优先排序，并且全部都是亚纳摩尔至低纳摩尔浓度的 HIV-1 抑制剂。对这些分子的详细生物学评估将与优化新先导分子的配方和递送的努力相结合，以及利用药物化学来提高所选化合物的溶解度、稳定性和生物利用度。化合物代谢和蛋白质结合的比较评估也将用于帮助优先考虑和确定下一代嘧啶二酮临床候选药物，该候选药物具有高度优化的药代动力学特性以及针对野生型、NNRTI 抗性和 MDR 病毒的最高可能效力。