Design & Synthesis of Protein Interacting Affinity Ligands and Protease Inhibitors

Abstract: There is a growing need of both protein drugs and synthetic drugs in the fight against many life-threatening diseases. The first part of this thesis deals with the design and synthesis of high affinity binding ligands for the purification of protein drugs. The second part describes design and synthesis of protease inhibitors targeting the cysteine protease cathepsin S and the serine protease hepatitis C NS3/4A.In work with parallel synthesis of new affinity chromatography ligands, indole was used as the scaffold for both solid phase and solution phase syntheses. A library of 1,3-disubstituted indoles was prepared via an iterative Mannich reaction sequence. The first Mannich reaction provided 3-aminomethylindoles, while the second Mannich reaction introduced an additional aminomethyl group at the N1 position of the indole ring. A library of 25 substituted indoles was prepared in moderate to good yields and purity.Inhibition of the cysteine protease cathepsin S is an attractive target for drug development of inhibitors having potential for regulation of autoimmune diseases and allergic disorders. Syntheses targeting the cysteine protease cathepsin S were performed by a solid phase approach. The structure-activity-relationships (SAR) of variations in the P3 sulfonamide part of 4-amidofuran-3-one inhibitors are presented. Several highly potent inhibitors were found, in both enzyme and cellular assays.The hepatitis C virus (HCV), causes a chronic liver condition which can lead to cirrhosis and liver cancer. The  serine protease hepatitis C NS3/4A is a promising target for development of HCV drugs. In the syntheses of novel HCV NS3/4A inhibitors, four new P2 substituents were first incorporated on a proline-based linear scaffold. The most potent P2 substituent, quinazoline, was evaluated in a larger study yielding more rigidified cyclopentane-based macrocyclic inhibitors. The SAR exercise resulted in several inhibitors with excellent potency in the low nanomolar range.