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

镰状细胞病(SCD)，由引起红细胞的血红蛋白(Hb)基因突变引起 (红细胞)变得畸形和僵硬(镰刀状)，影响大约10万美国人(和数百万 全球)，估计美国医疗保健系统每年的成本超过10亿美元。红血球在作怪， 下游SCD不良影响的主要原因，包括痛苦的危机、进行性器官损害，以及， 最终过早死亡，是脱氧“紧张”(T-)在细胞内聚合的结果 状态)镰刀型血红蛋白(HBS)(只有T状态的HBS倾向于聚合，而不是氧(O2)连接的 《轻松》(R-State)HBS)。因此，典型的红细胞镰状在低氧条件下发生。最近的 FDA批准Voxelotor是一类潜在的疾病修改药物中的第一种，为 SCD治疗方式的范式转变。在Voxelotor批准之前，没有 二十多年来，针对这种疾病的根本原因的新疗法。芳香醛- 含有化合物，如Voxelotor，通过变构结合到SCD和 稳定，HBS的高O2亲和力R-态，不聚合。使用迭代的、基于结构的 15年来，我们的药物化学家团队一直专注于开发芳香族化合物 通过合理修饰天然化合物具有增强治疗潜力的含醛类似物， 比如香草醛。在X射线共结晶学和分子模拟的指导下，香兰素衍生物 随着药效和作用时间的增加，已通过加入系链的吡啶部分而获得 具有不同的替换和修改。我们的主要候选药物VZHE-039是独一无二的，因为它不是 不仅通过氧依赖机制提供显著增加的Hb变构调节，而且还参与 在与HbαF-螺旋的分子间接触中，它通过O2直接破坏聚合物形成的稳定性 独立的机制。这种新的双重作用机制，并不单纯依赖氧气，具有 有可能提供更强大的抗病作用，而不会固有地限制组织氧气的卸载。 基于大量非常鼓舞人心的、初步的体外和体内数据，我们开发了一种 研究战略，将促进快速过渡到第二阶段SBIR研究，并随后 研究用新药(IND)申请。此第一阶段提案的主要目标是确定和评估 VZHE-039改善胃肠道溶解度和口服生物利用度的最佳口服处方。这个 优化的处方将在大鼠和小鼠身上进行评估，以确定其药代动力学和 单剂量口服给药和多次重复给药给药后的药效学特征 州政府。一种具有改进的体内口服生物利用度和最佳稳态动力学的试剂将准备好 SCD小鼠模型的明确疗效研究，以及高级哺乳动物的IND毒理学研究。

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.