The over-expression of matrix metalloproteinases (MMPs) is believed to contribute to tissue damage associated with rheumatoid and osteoarthritis. Although numerous peptide based MMP inhibitors have been described, most have shown poor oral activity in animal models and low bioavailability due to enzymatic hydrolysis of the labile amide backbones. The goal of this project is to address the underlying problems of MMP inhibitors by substituting the more traditional alpha-amino acid derived from backbones with enzymatically stable beta-amino acid analogs. The target compounds have been chosen based upon molecular modeling studies of beta-amino acid analogs manually docked into the K-ray crystal structure of the MM stromelysin-1. These beta-amino acid based inhibitors retain the essential stereochemical and functional features of known MMP inhibitors and should exhibit enhanced in vivo activity. While modern synthetic methods have produced several means to produce beta-amino acids, some new synthetic strategies are proposed which may expedite the efficient stereoselective construction of the target compounds. In addition, a novel solid phase strategy for the asymmetric synthesis of beta-amino acids is proposed. Using the methods outlined, a library of beta-amino acid derived compounds will be prepared and evaluated as stromelysin-1 inhibitors. Their stability toward hydrolytic enzymes will also be determined. The use of solid phase chemistry and screening should provide the best approach for the discovery and development of novel MMP inhibitors for the treatment of arthritic disease.
