Rapid Development of a Lead Aromatic Aldehyde Derivative with both Oxygen Dependent and Novel, Oxygen Independent Anti-Sickling Effects: Building on a Paradigm Shift in Sickle Cell Disease Therapy

快速开发具有氧依赖性和新颖的、氧独立抗镰状效应的先导芳香醛衍生物：以镰状细胞病治疗范式转变为基础

• 批准号: 10081656
• 负责人: James Burnett
• 金额: $ 30万
• 依托单位: ILLEXCOR THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-15 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10081656
• 关键词: Address; Adoption; Affect; Affinity; Aldehydes; American; Antisickling Agents; Attenuated; Binding; Bioavailable; Biological Availability; C57BL/6 Mouse; Cessation of life; Collection; Crystallography; DNA Sequence Alteration; Data; Deoxygenated Sickle Hemoglobin; Development; Disease; Disease model; Dose; Erythrocytes; Etiology; Excipients; Exhibits; Exposure to; Formulation; Foundations; Goals; Healthcare Systems; Hemoglobin; Hour; Hypoxia; Impairment; In Vitro; Individual; Investigational Drugs; Investigational New Drug Application; Kinetics; Lead; Ligands; Mammals; Measures; Modality; Modification; Mus; Oral; Organ; Organ failure; Oxygen; Pain; Pathologic; Patients; Performance; Pharmaceutical Preparations; Phase; Plasma; Play; Polymers; Property; Rattus; Research; Rodent; Roentgen Rays; Role; Safety; Scientist; Sickle Cell; Sickle Cell Anemia; Sickle Hemoglobin; Small Business Innovation Research Grant; Solubility; Sprague-Dawley Rats; Structure; Techniques; Testing; Therapeutic; Time; Tissues; Toxicology; Treatment Cost; Whole Blood; Work; adduct; analog; base; cost estimate; drug candidate; efficacy study; gastrointestinal; improved; in vivo; insight; malformation; molecular modeling; mouse model; new therapeutic target; novel; pharmacokinetics and pharmacodynamics; polymerization; premature; prevent; pyridine; scaffold; scale up; sickling; small molecule; therapeutic candidate; vanillin

Sickle cell disease (SCD), which results from a genetic mutation in hemoglobin (Hb) that causes red blood cells (RBCs) to become malformed and rigid (‘sickled’), affects approximately 100,000 Americans (and millions worldwide), with an estimated cost to the US healthcare system of over $1B annually. Red blood cell sickling, the primary cause of downstream adverse SCD effects, including painful crises, progressive organ damage, and, eventually premature death, is a consequence of the intracellular polymerization of deoxygenated “Tense” (T- state) sickle-type Hemoglobin (HbS) (only T-state HbS tends to polymerize and not oxygen (O2)-liganded “Relaxed” (R-state) HbS). Therefore, RBC sickling typically develops under conditions of hypoxia. The recent FDA approval of Voxelotor, the first in a new class of potentially disease-modifying drugs, sets the stage for a paradigm shift in the way SCD is therapeutically managed. Prior to the approval of Voxelotor, there had been no new therapeutics targeting the underlying cause of the disease in more than two decades. Aromatic aldehyde- containing compounds, such as Voxelotor, address the primary etiology of SCD by allosterically binding to, and stabilizing, the high O2 affinity R-state of HbS, which does not polymerize. Using an iterative, structure-based approach, our team of medicinal chemists has, for over 15 years, been focused on developing aromatic aldehyde-containing analogs with enhanced therapeutic potential by rationally-modifying natural compounds, such as vanillin. Guided by insights from X-ray co-crystallography and molecular modeling, vanillin derivatives with increasing potency and duration of action have been attained by incorporating a tethered pyridine moiety with diverse substitutions and modifications. Our lead therapeutic candidate, VZHE-039, is unique in that it not only provides significantly increased Hb allosteric modulation via an O2 dependent mechanism, but also engages in inter-molecular contacts with the Hb αF-helix, which directly destabilizes polymer formation via an O2 independent mechanism. This novel dual mechanism of action, which is not solely O2 dependent, has the potential to provide for even more potent anti-sickling effects without inherently limiting tissue O2 unloading. Based on a significant body of highly encouraging, preliminary in vitro and in vivo data, we have developed a research strategy that will facilitate a rapid transition to Phase II SBIR studies and, subsequently, an Investigational New Drug (IND) application. The principle goal of this Phase I proposal is to identify and evaluate an optimal oral formulation for VZHE-039 to improve gastrointestinal solubility and oral bioavailability. The optimized formulation will be evaluated in both rats and mice to determine its pharmacokinetic and pharmacodynamic profile with single oral doses of the drug, as well as multiple repeat dose exposure to steady state. An agent with improved in vivo oral bioavailability and optimal steady state kinetics will be ready for definitive efficacy studies in an SCD mouse model, as well as IND-enabling toxicology in higher order mammals.

镰状细胞病 (SCD)，由血红蛋白 (Hb) 基因突变引起，导致红细胞增多 （红细胞）变得畸形和僵化（“镰刀状”），影响了大约 100,000 名美国人（以及数百万人） 全球范围内），估计美国医疗保健系统每年的成本超过 1B 美元。 下游不良 SCD 效应的主要原因，包括痛苦危机、进行性器官损伤，以及， 最终过早死亡，是细胞内脱氧“Tense”（T- 态）镰状血红蛋白 (HbS)（只有 T 态 HbS 倾向于聚合，而不是氧 (O2) 配体） “松弛”（R 状态）HbS）因此，红细胞镰状化通常是在缺氧条件下形成的。 FDA 对 Voxelotor 的批准，是新型潜在疾病缓解药物中的第一个，为 在 Voxelotor 获得批准之前，SCD 的治疗管理方式没有发生过范式转变。 二十多年来针对该疾病根本原因的新疗法。 含有 Voxelotor 等化合物，通过变构结合来解决 SCD 的主要病因，并且 使用基于结构的迭代来稳定 HbS 的高 O2 亲和力 R 态。 15 年来，我们的药物化学家团队一直致力于开发芳香族化合物 通过合理修饰天然化合物来增强治疗潜力的含醛类似物， 例如香草醛，以 X 射线共晶学和分子模型的见解为指导，香草醛衍生物。 通过掺入束缚的吡啶部分，可以提高效力和作用持续时间 我们的主要治疗候选药物 VZHE-039 的独特之处在于它不是 不仅通过 O2 依赖性机制显着增加 Hb 变构调节，而且还参与 与 Hb αF 螺旋发生分子间接触，通过 O2 直接破坏聚合物形成的稳定性 这种新颖的双重作用机制不仅依赖于氧气，还具有以下特点： 具有提供更有效的抗镰状效应的潜力，而不会固有地限制组织的 O2 卸载。 基于大量令人鼓舞的初步体外和体内数据，我们开发了一种 研究战略将促进快速过渡到 II 期 SBIR 研究，并随后 研究性新药 (IND) 申请的第一阶段提案的主要目标是识别和评估。 VZHE-039 的最佳口服制剂，可提高胃肠道溶解度和口服生物利用度。 优化的制剂将在大鼠和小鼠中进行评估，以确定其药代动力学和 单次口服剂量的药物的药效学特征，以及多次重复剂量暴露于稳定的 具有改善的体内口服生物利用度和最佳稳态动力学的药物将准备就绪。 在 SCD 小鼠模型中进行明确的功效研究，以及在高等哺乳动物中进行 IND 毒理学研究。