SBIR-STTR Award

Allosteric effectors reduce the oxygen affinity of hemoglobin allowing for greater tissue oxygenation. The goal of the research program is to develop a new class of pharmaceutical agents that would be the first of their kind, which enhance tissue oxygenation. Many disease states would benefit significantly from an increase in cellular oxygen delivery. The overall intent of the phase I proposal will involve the design, synthesis, structural determination, and assessment of the biological efficacy of the potential allosteric modifiers of human HbA, for potential clinical uses. The specific goals will include: a) the rational design of novel allosteric modifiers of human hemoglobin, employing a structure-based approach and molecular modeling based on the X-ray crystallographic binding data of two lead molecules, RSR4 and RSR13, b) determination of the X-ray crystallographic binding of specific drug-HbA atom-atom interactions contributing to the allosteric activity of these compounds and c) the evaluation of the in vitro and in vivo pharmacologic and pharmacokinetic activity of these agents by measuring alterations in the whole blood oxygen affinity.

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.