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 microM, 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.
Leung-Toung
Regis
R
Department of Medicinal Chemistry, Apotex Research, Inc, 400 Ormont Drive, Toronto, Ontario, Canada M9L 1N9.
Wodzinska
Jolanta
J
Li
Wanren
W
Lowrie
Jayme
J
Kukreja
Rahul
R
Desilets
Denis
D
Karimian
Khashayar
K
Tam
Tim Fat
TF
D001665:Binding Sites; D002401:Cathepsin B / Q000037:antagonists & inhibitors*; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis / Q000145:classification / Q000494:pharmacology*; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry; D007700:Kinetics; D015394:Molecular Structure; D013830:Thiadiazoles / Q000138:chemical synthesis / Q000145:classification / Q000494:pharmacology*
D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides; D013830:Thiadiazoles; D002401:Cathepsin B