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ID: ALA1154163

Journal: Bioorg Med Chem Lett

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

Authors: Ameriks MK, Axe FU, Bembenek SD, Edwards JP, Gu Y, Karlsson L, Randal M, Sun S, Thurmond RL, Zhu J.

Abstract: 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.

CiteXplore: 19773165

DOI: 10.1016/j.bmcl.2009.09.014