SOUTH SAN FRANCISCO, Calif.--(BW HealthWire)--April 9, 2001--Axys Pharmaceuticals, Inc. (Nasdaq:AXPH - news) announced the publication of a paper describing the basis of a new technology for designing competitive and fully reversible serine protease inhibitors. The paper, entitled ``A Novel Serine Protease Inhibition Motif Involving a Multi-centered Short Hydrogen Bonding Network at the Active Site'' is published in the on-line issue of The Journal of Molecular Biology, and was authored by a team of seventeen Axys scientists led by Bradley Katz, Ph.D., a Staff Scientist and Group Leader in the Structural Chemistry department at Axys. The structure-based design paradigm describes novel small molecule scaffolds that bind tightly and preferentially to the active site of certain serine proteases by forming a highly organized network of short hydrogen bonds. This inhibitor-binding motif was confirmed at Axys with over 30 X-ray crystal structures of several serine proteases, including thrombin, trypsin and urokinase. The publication can be found on the Internet at www.idealibrary.com/links/toc/jmbi
``In the new approach to serine protease inhibitor design, inhibitor binding is mediated by an intricate network of hydrogen bonds, some of which are very short, providing the stability required for the inhibitor to bind to the enzyme as a long-lived complex,'' according to Michael C. Venuti, Ph. D., Senior Vice President of Research and Preclinical Development and Chief Technical Officer. ``This new approach is complementary to our previously published Delta technology which used zinc as a physiological source to anchor inhibitors at the active site of the protease. Both motifs vastly improve upon older approaches that formed more permanent covalent bonds to enzymes, making their action irreversible and as a result, relatively unsuitable as drugs for chronic disease. With each of the Axys inhibitor motifs, we are creating competitive and fully reversible inhibitors as confirmed by biochemical measurements, thereby meeting a key criteria for designing candidate molecules that represent potential breakthrough drugs.''
The new design motif has been applied in several ongoing Axys research and drug development programs to a variety of protease targets, including urokinase, Factor VIIa, and Factor Xa. Composition of matter patent applications has been filed to protect the specific compounds and intellectual property derived from these findings. Axys expects separate papers to be published in peer-reviewed journals describing the particular application of the new technology to the inhibition of urokinase and Factor Xa, both active preclinical programs at the company.
Axys believes that the new scaffold has broad application to important pharmaceutical targets as the new motif-designed inhibitors meet key criteria for drug development candidates early in the discovery process. Like the Delta technology, which remains the basis for oral inhibitors of tryptase under preclinical study by Bayer AG, the new scaffold design paradigm yields inhibitors that are non-peptide, not dependent on chiral centers for activity, and have low molecular weights. All of these factors contribute to a compound profile exhibiting excellent pharmacokinetic parameters that allow once-a-day dosing in experimental systems, and evidence of oral bioavailability.... |
