Critical care medicine (e.g., treatment of stroke, heart attack) was Inotek’s discovery focus when founded nearly 20 years ago. The company identified three major pharmacologic targets for intervention (adenosine, PARP, and reactive oxygen species including peroxynitrite), each of which regulate or arise as cellular responses to tissue stress or injury, including elevated intraocular pressure, hypoxia (low oxygen), ischemia-reperfusion, and oxidative stress from hyperglycemic metabolism (e.g., in diabetes). These pathologies alter cellular metabolism and energetics, activate inflammation, and result in DNA damage and often cell death. Of these three pharmacologic targets, Inotek has chosen to focus its development efforts on advancing product candidates that mimic the protective actions of adenosine.
Adenosine Mimetics as Product Candidates for Glaucoma.
Adenosine is an important extracellular signaling molecule that participates in a wide variety of physiological and pathological processes. Adenosine has many biological effects, which are mediated through activity at four known adenosine-specific receptor subtypes: A1, A2a, A2b and A3. These receptors are present throughout the body on the cells of different tissues, and at different levels of expression. Under metabolically stressful conditions, such as those that occur during injury, ischemia, and inflammation, adenosine’s extracellular concentration increases dramatically suggesting a compensatory protective effect.
Inotek’s scientists began to deconstruct the complex adenosine biology to isolate the protective activity of adenosine, and consequently to build this into novel therapeutics. Beginning with adenosine’s chemical structure, our team worked to create a series of small molecules that very selectively bind to the different adenosine receptor subtypes. By doing so, our molecules were able to produce the specific biological effects associated with stimulation of only a single adenosine receptor subtype. In this way, the undesired biological actions of native adenosine (e.g., stimulation of either the A2a or A3 receptors increasing, rather than decreasing, intraocular pressure, which is often elevated in glaucoma patients) were systematically removed. Our process of rational drug design was enabled by a deep understanding of the relationship between the chemical structure of our adenosine mimetics, and their ability to bind and activate each adenosine receptor subtype. Ultimately, product candidates emerged from these efforts with specialized activity, including some adenosine mimetics that only modulated the A1 receptor subtype. The most advanced in development of these small molecules being trabodenoson (formerly known as INO-8875).