Pharmacological inhibitors of restenosis following balloon angioplasty are needed to inhibit the proliferation smooth muscle cells. Lion Pharmaceuticals and its collaborators Dr. Chatters at Johns Hopkins University propose to develop inhibitors based on novel enzymatic drug target UDP-galactose: glucosylceramide, Beta-1-4 galactosyltransferase (GalT-2; LacCer synthase). The mitogenic stimulation of the muscle cells leads to elevated levels of GalT-2 activity and its product LacCer, appear to act as both a second messenger and a mitogen in its own right. The primary hypothesis in this grant is that inhibition of GalT-2 following balloon angioplasty should reduce and or prevent restenosis. A combinatorial library of approximately 500 compounds based on the structure of a non-selective inhibitor, D-PDMP, will be screened against a partially purified preparation of GalT-2. Candidate inhibitors from the screening process will be tested for their effectiveness in preventing smooth muscle cells proliferation. Specificity of candidate inhibitors for GalT-2 will then be evaluated by screening a family of unrelated enzymes that are important intracellular enzymes. Based on these studies they will proceed with Phase II testing in animal models of restenosis and initiate both formulation and safety studies in order to complete an attractive package for outlicensing and commercialization by Lion.
Thesaurus Terms: cardiovascular agent, cell proliferation, drug screening /evaluation, enzyme inhibitor, restenosis, vascular smooth muscle chemical registry /resource, galactosyltransferase, heart disorder chemotherapy scintillation counter, tissue /cell culture
