1,2,4-thiadiazole: A novel Cathepsin B inhibitor

A novel class of Cathepsin B inhibitors has been developed with a 1,2,4-thiadiazole heterocycle as the thiol trapping pharmacophore. Several compounds with different dipeptide recognition sequence (i.e., P1'-P2' = Leu-Pro-OH or P2-P1=Cbz-Phe-Ala) at the C5 position and with different substituents (i.e., OMe, Ph, or COOH) at the C3 position of the 1,2,4-thiadiazole ring have been synthesized and tested for their inhibitory activities. The substituted thiadiazoles 3a-h inhibit Cat B in a time dependent, irreversible manner. A mechanism based on active-site directed inactivation of the enzyme by disulfide bond formation between the active site cysteine thiol and the sulfur atom of the heterocycle is proposed. Compound 3a (K-i = 2.6 muM, k(i)/K-i = 5630 M-1 s(-1)) with a C3 methoxy moiety and a Leu-Pro-OH dipeptide recognition sequence, is found to be the most potent inhibitor in this series. The enhanced inhibitory potency of 3a is a consequence of its increased enzyme binding affinity (lower K-i) rather than its increased intrinsic reactivity (higher k(i)). In addition, 3a is inactive against Cathepsin S, is a poor inhibitor of Cathepsin H and is > 100-fold more selective for Cat B over papain. (C) 2003 Elsevier Ltd. All rights reserved.