Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
24
pubmed:dateCreated
2005-11-23
pubmed:abstractText
The lysosomal cysteine protease cathepsin K is a target for osteoporosis therapy. The aryl-piperazine-containing cathepsin K inhibitor CRA-013783/L-006235 (1) displays greater than 4000-fold selectivity against the lysosomal/endosomal antitargets cathepsin B, L, and S. However, 1 and other aryl-piperazine-containing analogues, including balicatib (10), are approximately 10-100-fold more potent in cell-based enzyme occupancy assays than against each purified enzyme. This phenomenon arises from their basic, lipophilic nature, which results in lysosomal trapping. Consistent with its lysosomotropic nature, 1 accumulates in cells and in rat tissues of high lysosome content. In contrast, nonbasic aryl-morpholino-containing analogues do not exhibit lysosomotropic properties. Increased off-target activities of basic cathepsin K inhibitors were observed in a cell-based cathepsin S antigen presentation assay. No potency increases of basic inhibitors in a functional cathepsin K bone resorption whole cell assay were detected. Therefore, basic cathepsin K inhibitors, such as 1, suffer from reduced functional selectivities compared to those predicted using purified enzyme assays.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
http://linkedlifedata.com/resource/pubmed/chemical/Benzamides, http://linkedlifedata.com/resource/pubmed/chemical/Bone Density Conservation Agents, http://linkedlifedata.com/resource/pubmed/chemical/CTSK protein, human, http://linkedlifedata.com/resource/pubmed/chemical/CTSL1 protein, human, http://linkedlifedata.com/resource/pubmed/chemical/Cathepsin B, http://linkedlifedata.com/resource/pubmed/chemical/Cathepsin K, http://linkedlifedata.com/resource/pubmed/chemical/Cathepsin L, http://linkedlifedata.com/resource/pubmed/chemical/Cathepsins, http://linkedlifedata.com/resource/pubmed/chemical/Ctsk protein, mouse, http://linkedlifedata.com/resource/pubmed/chemical/Ctsk protein, rat, http://linkedlifedata.com/resource/pubmed/chemical/Ctsl protein, mouse, http://linkedlifedata.com/resource/pubmed/chemical/Ctsl protein, rat, http://linkedlifedata.com/resource/pubmed/chemical/Cysteine Endopeptidases, http://linkedlifedata.com/resource/pubmed/chemical/Morpholines, http://linkedlifedata.com/resource/pubmed/chemical/N-(1-(((cyanomethyl)amino)carbonyl)c..., http://linkedlifedata.com/resource/pubmed/chemical/Piperazines, http://linkedlifedata.com/resource/pubmed/chemical/Thiazoles, http://linkedlifedata.com/resource/pubmed/chemical/cathepsin S
pubmed:status
MEDLINE
pubmed:month
Dec
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:day
1
pubmed:volume
48
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
7535-43
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed-meshheading:16302795-Animals, pubmed-meshheading:16302795-Antigen Presentation, pubmed-meshheading:16302795-Autoradiography, pubmed-meshheading:16302795-Benzamides, pubmed-meshheading:16302795-Bone Density Conservation Agents, pubmed-meshheading:16302795-Cathepsin B, pubmed-meshheading:16302795-Cathepsin K, pubmed-meshheading:16302795-Cathepsin L, pubmed-meshheading:16302795-Cathepsins, pubmed-meshheading:16302795-Cell Line, pubmed-meshheading:16302795-Cysteine Endopeptidases, pubmed-meshheading:16302795-Female, pubmed-meshheading:16302795-Humans, pubmed-meshheading:16302795-Lysosomes, pubmed-meshheading:16302795-Mice, pubmed-meshheading:16302795-Mice, Inbred C57BL, pubmed-meshheading:16302795-Morpholines, pubmed-meshheading:16302795-Piperazines, pubmed-meshheading:16302795-Rabbits, pubmed-meshheading:16302795-Rats, pubmed-meshheading:16302795-Structure-Activity Relationship, pubmed-meshheading:16302795-Thiazoles, pubmed-meshheading:16302795-Tissue Distribution
pubmed:year
2005
pubmed:articleTitle
Lysosomotropism of basic cathepsin K inhibitors contributes to increased cellular potencies against off-target cathepsins and reduced functional selectivity.
pubmed:affiliation
Department of Biochemistry, Merck Frosst Centre for Therapeutic Research, Kirkland, Quebec, Canada.
pubmed:publicationType
Journal Article