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Peroxynitrite
- INO-4885 (formerly WW-85)
Reactive oxidant and free radical species play a major role in disease pathogenesis. Two types of reactive species are produced in response to inflammation, ischemic, and reperfusion injury:
v oxygen-centered species (superoxide, hydrogen peroxide)
v nitrogen-centered species (peroxynitrite, nitroxyl anion)
Oxidants exhibit a wide array of tissue-damaging cytotoxic effects, reacting with and attacking a variety of biomolecules, including proteins, lipids, and DNA. Low concentrations of oxidants usually trigger apoptotic death, whereas higher concentrations induce necrosis with cellular energetics (ATP and NAD) serving as a switch between the two modes of cell death. At higher concentrations, oxidants damage DNA, triggering the activation of DNA repair systems including poly(ADP-ribose) polymerase (PARP). Oxidant-induced overactivation of PARP consumes NAD+ and consequently ATP, culminating in cell dysfunction and necrosis.
Oxidants can also stimulate inflammatory gene expression and have a profound effect on protein function, via the oxidation or nitration of critical amino acid residues. Peroxynitrite can also trigger the activation of metalloproteinases via post-translational nitrosation. Oxidants have no other apparent physiological function. The association of peroxynitrite and other damaging oxidants (including hydroxyl, nitroxyl anion, and hydrogen peroxide) with a variety of important clinical conditions has been well established. These conditions include acute conditions such as acute myocardial infarction and organ transplantation and chronic conditions associated with progressive tissue damage, such as age-related macular degeneration, arthritis, and diabetes mellitus.
Recent work in the field, conducted in part by Inotek researchers, has pioneered the now widely-accepted concept that it is ONOO-, the toxic by-product of NO and O2-, rather than the free radicals that are responsible for much of the free radical-related cytotoxicity in inflammation and reperfusion injury. Because of the extremely high reactivity of ONOO- and some of the other oxidant species that are produced in various disease conditions, prior efforts to identify and develop catalytic agents that have sufficiently rapid reaction kinetics and present with an acceptable toxicity profile have been unsuccessful. The combination of the formation and reaction characteristics of peroxynitrite (rapid formation, relatively long biological half-life, ability of the species to cross biological membranes and thereby transmit the toxicity of its precursors, as well as its multiple biological targets and self-amplifying cascades of cytotoxic reactions initiated by them) represent a prime target for drug development.
Since ONOO- is produced in multiple disease conditions, its neutralization can be viewed as a platform technology, applicable across a wide variety of diseases. The requirements for the development of Inotek’s ONOO- decomposition catalysts included (1) high reactivity (rate constant), (2) catalytic nature of reaction, (3) low cytotoxicity, (4) additional neutralizing actions on other, relevant oxidant and free radical species (O2-, H2O2, NO-), in order to achieve broad spectrum effects, (5) ease of synthesis and analysis, and (6) optimal pharmacokinetic profile in vivo.
Inotek has discovered and developed a series of compounds representing a new class of metalloporphyrinic agents. First generation products were used to provide proof of concept in preclinical testing and demonstrated the broad applicability of our concept to myocardial infarction, chronic heart failure, diabetes, colitis, arthritis, and diabetic complications. Inotek has advanced a lead candidate, INO-4885, which has entered Phase 1 clinical trials.
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