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Bioorg Med Chem Lett. 2009 Nov 1;19(21):6135-9. doi: 10.1016/j.bmcl.2009.09.013. Epub 2009 Sep 10.

Pyrazole-based arylalkyne cathepsin S inhibitors. Part II: optimization of cellular potency.

Author information

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

Abstract

Basic lipophilic substituents dramatically improved the cellular potency of a previously disclosed series of pyrazole-based arylalkyne cathepsin S inhibitors. The incorporation of substituted benzylamines in the para position of the arylalkyne maintained enzymatic activity (hCatS IC50=80-420 nM) and imparted cellular potency (IC50=0.8-4.0 microM). Further refinement of the morpholine portion of the pharmacophore enabled the identification of bicyclic piperidines with enhanced affinity for CatS (IC50=10-30 nM) and sub-micromolar cellular potency (JY Ii IC50=200-720 nM).

PMID:
19783435
DOI:
10.1016/j.bmcl.2009.09.013
[Indexed for MEDLINE]

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