Therapeutic potential of adenosine kinase inhibition —Revisited

AbstractAdenosine (ADO) is an endogenous protective regulator that restores cellular energy balance in response to tissue trauma. Extracellular ADO has a half ‐life of the order of seconds thus restricting its actions to tissues and cellular sites where it is released. Adenosine kinase (AK, ATP:adenosine 5′‐phosphotransferase, EC 2.7.1.20) is a cytosolic enzyme that is the rate‐limiting enzyme controlling extracellular ADO concentrations. Inhibiti on of AK can effectively increase ADO extracellular concentrations at tissue sites where pathophysiological changes occur. Highly potent and selective nucleoside and non‐nucleoside AK inhibitors were discovered in the late 1990s that showed in vivo effects consistent with the augmentation of the a ctions of endogenous ADO in experimental models of pain, inflammation, and seizure activity. These data supported clinical development of several AK inhibitors for the management of epilepsy and chronic pain. However, early toxicological data demonstrated that nucleoside and non‐nucleoside chemoty pes produced hemorrhagic microfoci in brain in an apparent ADO receptor‐dependent fashion. An initial oral report of these important toxicological findings was presented at an international conference but a detailed description of these data has not appeared in the peer‐reviewed literature. In t he two decades following the demise of these early AK‐based clinical candidates, interest in AK inhibition has renewed based on preclin...
Source: Pharmacology Research and Perspectives - Category: Drugs & Pharmacology Authors: Tags: INVITED REVIEW Source Type: research