Highest Known Catalytic Rate for Superoxide Dismutation Achieved

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Highest Known Catalytic Rate for Superoxide Dismutation AchievedResearchers Use Computer-Aided Design to Create More Active Compound

St. Louis, MO, April 25, 2001 -- Researchers at MetaPhore Pharmaceuticals have used computer-aided design techniques to achieve a hundred-fold increase in the catalytic activity of one of the company's synthetic manganese-based compounds previously shown to exert protective anti-inflammatory effects in animal models.

The compounds, part of a family being developed by Metaphore, mimic the action of the body's prime free radical fighting natural enzyme, superoxide dismutase (SOD). The original SOD mimetic compound developed by Metaphore achieved catalytic rates approaching natural SOD.

"The improved compound possesses the highest catalytic rate for superoxide dismutation of any known synthetic mimetic," said lead researcher, Dennis Riley, adding that the improved compound also exceeds the catalytic rate of natural copper, zinc and manganese SOD enzymes because it "actually increases in catalytic rate as the pH decreases."

In a study published this month by the journal Inorganic Chemistry, the researchers also reported that the improved SOD enzyme mimetic, consistent with its enhanced catalytic rate, exhibited protective effects in animal models of reperfusion injury and septic shock at dosage levels one hundred times less than those required using the original SOD enzyme mimetic.

The lower dosage plus retention of the original's high degree of stability makes the improved SOD mimetic an even more attractive candidate for use as a drug in humans.

Riley and his team used computer-aided design processes, developed based on their unique understanding of how the original SOD mimetic functions as a catalyst, to circumvent the time consuming and expensive process of synthesizing and then testing countless molecular variations.

"Once we understood the subtle and unobvious interplay between position, number and spatial arrangement of atoms and groups in dictating a molecule's catalytic activity, we were able to design highly complicated molecules and test their potential as catalysts," explained Riley.

"Thus, we are now able to model any given molecular variation and calculate the expected catalytic rate," said Riley, "thereby giving us the capability to tailor a wide range of highly effective, very stable SOD mimetics for different disease states where free radical damage plays a role."

The SOD enzyme plays a central role in the body's oxidative chemistry, regulating normal levels of free radical superoxide molecules. In certain disease states, however, the body's immune system prompts an overproduction of superoxide free radicals and the natural SOD enzymes become overwhelmed, leading to tissue and cell damage.

Background

Production of superoxide, a free radical, results from cellular oxidative metabolism. However, when too much superoxide is produced in the body, various biomolecules, cell structures and even genes are damaged. Free-radical damage has been linked with a wide range of diseases and conditions, including autoimmune and neurodegenerative disorders, multiple types of cancer, complications of diabetes mellitus, strokes, reperfusion injury, as well as pain and inflammation.

One of the body's primary defense mechanisms against free-radical damage is the superoxide dismutase (SOD) family of enzymes. These enzymes typically regulate normal levels of superoxide by converting it into hydrogen peroxide and oxygen, also reducing production of related damaging oxidants, such as peroxynitrite.

MetaPhore is developing a proprietary family of drugs that mimic the catalytic activity of SOD to address the diseases and conditions resulting from excessive superoxide production. In pre-clinical models, the lead candidate from this family has suggested the potential to combat such diseases and conditions more effectively and with fewer side effects than existing treatments.

"SOD enzyme mimetics have major medical potential, based on the growing body of anti-oxidant and disease research. For more than twenty years, we have understood the free-radical fighting power of the body's natural SOD enzymes, but until recently, we have been unable to reproduce that beneficial effect in a stable and selective drug form," said Dennis Riley, MetaPhore's Senior Vice President of Research & Development.

MetaPhore's SOD enzyme mimetics are well suited for use as drugs because they have a low molecular weight, are highly stable and do not appear to elicit an immune response in the body.

Animal studies published in journals such as Science and the Proceedings of the National Academy of Sciences during the past few years have confirmed the disease fighting potential of MetaPhore's SOD enzyme mimetics. These studies have also demonstrated that MetaPhore's original SOD enzyme mimetic substantially reduces tissue damage due to inflammation and reperfusion injury -- the latter involving the return of blood flow following removal of blockade, such as after an ischemic heart attack or stroke.

Statements in this press release that are not strictly historical are "forward looking" statements as defined in the Private Securities Litigation Reform Act of 1995. The actual results may differ from those projected in the forward looking statement due to risks and uncertainties that exist in the company's operations, development efforts and business environment.

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