DESIGN & DEVELOPMENT OF HEMOGLOBIN ALLOSTERIC EFFECTORS

描述（改编自申请人摘要）：Allos Therapeutics是 开发新的专利药物来治疗 通过降低血红蛋白-氧亲和力从而卸载 更多的氧气从血液输送到缺氧组织 I期完成的研究 已经确定RSR 13是Allos的主要化合物。 RSR 13将用于 在接受低温心肺转流术的患者中进行的临床试验， 冠状动脉搭桥手术 另一个具体目标将涉及 研究以支持设计、发现和开发潜在的 在血红蛋白的新发现的结合位点上具有活性的治疗剂 四音步 非临床药理学研究表明，RSR 13确实 增加正常组织氧合，最大限度地增加O2消耗 锻炼骨骼肌，使低血糖引起的02 卸载能力的血红蛋白，削弱功能和代谢 由于心肌血流量减少而导致的缺陷， 体外循环，RSR 13在低温含血心脏停搏液中 显著增加心肌ATP含量， 乳酸/丙酮酸比率（改善氧化代谢）和改善恢复 收缩和舒张心室功能和电生理 功能 I期研究还检查了氧气中的药理作用 亲和力（p50），这与RSR 13给药的大鼠中 使用脉搏血氧仪测量血红蛋白饱和度。 RSR 13被发现可以减少 体内血红蛋白的氧亲和力。 此外，药效学数据 从比格犬中获得的p50显示出明显的剂量相关性增加 在施用RSR 13之后。 详细资料载于 使用RSR 13的拟议临床试验，包括总体研究设计， 患者人群，治疗组。 纳入和筛选新 提出了使用RSR 13的类似物作为 潜在的第二代血红蛋白合成变构调节剂。 拟议的商业应用：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.