DESIGN & DEVELOPMENT OF HEMOGLOBIN ALLOSTERIC EFFECTORS

描述(改编自申请者摘要)：Allas Treeutics is 开发治疗慢性阻塞性肺疾病临床症状的新型专利药物 通过降低血红蛋白-氧亲和力从而卸载而造成的缺氧 血液中的氧气更多地流向缺氧组织。第一阶段已完成的研究 已经确定RSR13是Allas的先导化合物。RSR13将用于 低温体外循环心脏直视手术的临床研究 冠状动脉搭桥术。另一个具体目标将涉及 支持设计、发现和开发潜力的研究 作用于新发现的血红蛋白结合部位的治疗剂 四分音节。非临床药理学研究表明，RSR13具有 增加正常组织的氧合，最大限度地增加02的消耗 锻炼骨骼肌，使02年低温引起的下降正常化 排出血红蛋白的能力，削弱功能和代谢。 心肌血流量减少所致的缺陷以及在犬 体外循环，RSR13在低温血液停搏液中 显著增加心肌组织中三磷酸腺苷含量，降低心肌组织 乳酸/丙酮酸比率(改善氧化代谢)并提高回收率 收缩和舒张期心功能和电生理 功能。第一阶段的研究还检查了氧气中的药理作用。 RSR13对大鼠亲和力(P50)的影响 脉搏血氧饱和度测定法测定血红蛋白饱和度。RSR13被发现降低了 体内血红蛋白的氧亲和力。此外，药效学数据 从Beagle狗身上获得的数据显示，p50明显随剂量增加而增加。 在实施RSR13之后。有关详细信息，请访问 采用RSR13的拟议临床试验，包括总体研究设计， 患者群体，治疗组。收录和筛选新的 化合物建议使用RSR13的类似物作为 潜在的第二代血红蛋白合成变构修饰剂。 建议的商业应用：不可用。

DESCRIPTION (Adapted from applicant's abstract): Allos Therapeutics is developing new, proprietary pharmaceuticals to treat clinical conditions of oxygen-deprivation by reducing hemoglobin-oxygen affinity thereby unloading more oxygen from the blood to hypoxic tissue. Studies completed in Phase I have identified RSR13 as the lead compound for Allos. RSR13 will be used in a clinical trial in patients undergoing hypothermic cardiopulmonary bypass for coronary artery bypass graft surgery. An additional specific aim will involve studies to support the design, discovery and development of potential therapeutic agents active at a newly discovered binding site of the hemoglobin tetrameter. Non-clinical pharmacology studies have shown that RSR13 does increase normal tissue oxygenation, increases 02 consumption in maximally exercising skeletal muscle, normalizes the hypothermia-induced decrease in 02 unloading capacity of hemoglobin, attenuates the functional and metabolic deficiencies due to reduced myocardial blood flow and in a canine model of cardiopulmonary bypass, RSR13 in the hypothermic-blood cardioplegia solution significantly increases myocardial ATP content, decreases the myocardial lactate/pyruvate ratio (improved oxidative metabolism) and improves recovery of systolic and diastolic ventricular function and electrophysiologic function. Phase I studies also examined the pharmacological effects in oxygen affinity (p50) in rats dosed with RSR13 which was correlated with changes in hemoglobin saturation using pulse oximetry. RSR13 was found to decrease the oxygen affinity of hemoglobin in vivo. In addition pharmacodynamic data obtained from Beagle dogs demonstrated a clear dose-related increase in p50 after the administration of RSR13. Detailed information is provided on the proposed clinical trials employing RSR13, including overall study design, patient populations, treatment groups. Inclusion and screening of new chemical compounds are proposed using analogs of RSR13 as potential second generation synthetic allosteric modifiers of hemoglobin. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE.