Pyrazole-based cathepsin S inhibitors with arylalkynes as P1 binding elements.

Publication Type:

Journal Article


Bioorg Med Chem Lett, Volume 19, Issue 21, p.6131-4 (2009)


Amino Acid Substitution, Binding Sites, Cathepsins, Crystallography, X-Ray, Drug Design, Humans, Mutagenesis, Site-Directed, Protease Inhibitors, Pyrazoles, Pyridines, Recombinant Proteins, Structure-Activity Relationship


<p>A crystal structure of 1 bound to a Cys25Ser mutant of cathepsin S helped to elucidate the binding mode of a previously disclosed series of pyrazole-based CatS inhibitors and facilitated the design of a new class of arylalkyne analogs. Optimization of the alkyne and tetrahydropyridine portions of the pharmacophore provided potent CatS inhibitors (IC50=40-300 nM), and an X-ray structure of 32 revealed that the arylalkyne moiety binds in the S1 pocket of the enzyme.</p>