Plexxikon Highlights Research Findings Key to Drug Discovery for Phosphodiesterase Targets; Robust Discovery Platform Accelerates Development of Selective Inhibitors for Respiratory Disease.

Business Editors/Health/Medical Writers

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PRINCETON, N.J.--(BUSINESS WIRE)--Nov. 13, 2003

Plexxikon Inc., a privately held drug discovery company, today presented research results from the company's drug discovery program involving the discovery and development of drug candidates targeting phosphodiesterase (PDE) enzymes at the Strategic Research Institute's "Phosphodiesterases in Disease" Conference in Princeton, New Jersey. Structural analysis completed by Plexxikon scientists reveals new data that explains the selectivity of potential drug candidates thereby providing key insights for the design and development of new drugs that target any member of the PDE family. Additionally, Plexxikon presented initial in vivo efficacy data for the company's novel, selective PDE 4 inhibitors for the treatment of chronic obstructive pulmonary disease (COPD) showing over 80% inhibition.

"Plexxikon's drug discovery success to date is the result of the establishment of a robust structure determination platform and its integration into a state-of-the-art drug discovery engine," said Michael V. Milburn, Ph.D., senior vice president, research, at Plexxikon. "Particularly in our PDE program, we have been very successful in rapidly generating several novel chemotypes for our PDE 4 inhibitor program, having produced gram quantities of crystallography-grade protein, developed assays for the entire family of PDE proteins, solved over 50 co-structures for a number of PDEs as well as determined the first high-resolution crystal structures for PDE 1 and PDE 10."

Plexxikon Findings Accelerate Development of Novel PDE Inhibitors

Recent research studies conducted by Plexxikon scientists have provided key drug discovery insights that have led to the rapid development by Plexxikon of three novel drug lead series targeting PDE 4, a target validated for the treatment of COPD and asthma. Utilizing co-crystallography in which a compound is bound to a protein target, crystallized and X-rayed, Plexxikon has determined the mode of nucleotide binding to both the cAMP-selective PDE 4 family, and to the cGMP-selective PDE 5 enzyme. This work highlights the unique role of a key glutamine, a single amino acid in the binding site of all PDEs that can be exploited to enhance drug selectivity. Furthermore, a 'hydrophobic clamp' has been identified, an area of the PDE binding site that provides a critical component of the interaction both with PDE drugs as well as the natural ligands. Additionally, Plexxikon has completed co-structure analysis of a number of compounds previously developed by others with PDE 4B, including Rolipram, Cilomilast and Piclamilast.

Promising In Vivo Efficacy Data for PDE 4 Inhibitor

Plexxikon is developing PDE 4 inhibitors that are selective for PDE 4B. Previously, drugs targeting PDE 4 have not been selective for PDE 4B. It is believed that activity against PDE 4D, which is structurally very similar, has led to dose-limiting toxicities. With the high resolution of the company's three-dimensional structures, Plexxikon has been able to design potential drug candidates that selectively inhibit PDE 4B, despite over 90% identity between the PDE 4B and PDE 4D catalytic domains.

Plexikon's initial PDE 4 compounds have been tested in a model of inflammation in rats and demonstrated over 80% inhibition compared to control. These compounds are being developed for the potential treatment of COPD and are undergoing further optimization. In addition to their broad use as anti-inflammatory therapeutics, PDE 4 inhibitors also have potential therapeutic value in several CNS indications and in oncology. The company expects to initiate human clinical trials testing its PDE 4 inhibitor in 2005.

Selective PDE 5 Inhibitor in Lead Discovery

Plexxikon also has advanced selective inhibitors of PDE 5A to lead discovery. PDE 5A is the validated target of several drugs on the market for the treatment of erectile dysfunction, including Viagra(R), Levitra(R) and Cialis(R). Current marketed drugs show activity against PDE 5A, but also inhibit the closely related families PDE 6 and PDE 11. This "off target" activity appears to cause certain side effects, including blue-tinged vision, muscle and back pain. Plexxikon has solved co-structures of PDE 5A with Viagra(R), Levitra(R) and Cialis(R) at resolutions of 1.3 A, 1.78 A and 1.37 A, respectively, higher than any published to date. This structural information provides Plexxikon a key competitive advantage in designing more selective compounds targeting PDE 5A to eliminate potential side effects. In addition to sexual dysfunction, PDE 5 inhibitors have potential therapeutic value in the treatment of cardiovascular disorders.

About Plexxikon

Plexxikon is a leader in the discovery and development of novel small molecule pharmaceuticals to treat human disease. Plexxikon's proprietary Scaffold-Based Drug Discovery(TM) platform is being applied to identify and build a portfolio of product opportunities for the treatment of metabolic disorders, cardiovascular disease, inflammation and oncology. This discovery process utilizes a number of technologies, including structural screening as one key component that provides a significant competitive advantage to other drug discovery approaches.

Currently, the company's most advanced programs include a PPAR pan-agonist for the treatment of diabetes and related cardiovascular complications, and a PDE 4B selective inhibitor for the treatment of chronic obstructive pulmonary disease (COPD). Plexxikon anticipates initiating human trials for both these programs in 2005. Plexxikon is seeking pharmaceutical and biotechnology partners for a variety of collaboration opportunities, including the development of compounds for any target of interest to such partners. For more information, please visit www.plexxikon.com.

Note: The symbol A in this news release should be read as Angstrom.