Many life-threatening medical conditions are associated with injury or damage to vital organs, such as myocardial infarction in the heart, stroke in the brain, and acute failure of the kidneys. These are emergency situations for the body because the affected organ(s) experiences a sudden lack of sufficient oxygen and nutrients, which can lead to cell death, tissue damage, and organ failure.

FibroGen has identified a series of proprietary HIF-PH inhibitors that through the stabilization of HIF upregulate gene arrays important in eliciting an immediate response to hypoxia. The protein products of these genes are involved in protecting cells and tissues from the dangerous consequences of hypoxia, providing benefits such as cytoprotection, prevention of apoptosis (programmed cell death) and free radical damage, and renoprotection.

HIF stabilization also leads to alterations in energy metabolism that lower oxygen utilization and induce a shift toward mobilization and metabolism of higher energy fat stores. For example, HIF-mediated enzymatic pathways can shift energy production away from aerobic glycolysis, reducing cellular oxygen consumption by as much as 50% in vitro. These acute mechanisms act to limit damage from short-term oxygen deprivation, while chronic HIF-mediated responses, including the formation of new blood vessels, help to restore normal oxygen delivery to the organism.

Thus, the pharmacological stabilization of HIF offers an attractive approach to stimulating the type of multifactorial response that is expected to provide therapeutic benefit in treating organs and tissues that experience potentially life-threatening oxygen deprivation. In cases where potential for tissue injury can be predicted, such as with elective surgical procedures (e.g., coronary interventions), a pre-treatment approach based on HIF stabilization could be used to enhance the resistance of an organ or tissue to injury and to prevent further damage from reperfusion injury.

In vivo experiments using certain of FibroGen proprietary HIF stabilizers demonstrate the therapeutic benefit of these compounds in protecting tissues and maintaining organ function in relevant animal models, including myocardial infarction, permanent and transient ischemic stroke, renal ischemia reperfusion injury, and radiocontrast nephrotoxicity.