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Bioorg Med Chem Lett. 2009 Nov 1;19(21):6131-4. doi: 10.1016/j.bmcl.2009.09.014. Epub 2009 Sep 10.

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

Author information

1
Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA. mameriks@its.jnj.com

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.

PMID:
19773165
DOI:
10.1016/j.bmcl.2009.09.014
[Indexed for MEDLINE]

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