title: 1,2,4-thiadiazole: a novel Cathepsin B inhibitor.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Apotex Research, Inc, 400 Ormont Drive, Toronto, Ontario, Canada M9L 1N9.
authors.forename: Regis
authors.initials: R
authors.lastname: Leung-Toung
authors.forename: Jolanta
authors.initials: J
authors.lastname: Wodzinska
authors.forename: Wanren
authors.initials: W
authors.lastname: Li
authors.forename: Jayme
authors.initials: J
authors.lastname: Lowrie
authors.forename: Rahul
authors.initials: R
authors.lastname: Kukreja
authors.forename: Denis
authors.initials: D
authors.lastname: Desilets
authors.forename: Khashayar
authors.initials: K
authors.lastname: Karimian
authors.forename: Tim Fat
authors.initials: TF
authors.lastname: Tam
mesh_terms: 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*
chemical_list: D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides; D013830:Thiadiazoles; D002401:Cathepsin B