DESIGN & DEVELOPMENT OF HEMOGLOBIN ALLOSTERIC EFFECTORS

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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.