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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
5
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pubmed:dateCreated |
2001-3-23
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pubmed:abstractText |
Cathepsin K (EC 3.4.22.38), a cysteine protease of the papain superfamily, is predominantly expressed in osteoclasts and has been postulated as a target for the treatment of osteoporosis. Crystallographic and structure--activity studies on a series of acyclic ketone-based inhibitors of cathepsin K have led to the design and identification of two series of cyclic ketone inhibitors. The mode of binding for four of these cyclic and acyclic inhibitors to cathepsin K is discussed and compared. All of the structures are consistent with addition of the active site thiol to the ketone of the inhibitors with the formation of a hemithioketal. Cocrystallization of the C-3 diastereomeric 3-amidotetrahydrofuran-4-one analogue 16 with cathepsin K showed the inhibitor to occupy the unprimed side of the active site with the 3S diastereomer preferred. This C-3 stereochemical preference is in contrast to the X-ray cocrystal structures of the 3-amidopyrrolidin-4-one inhibitors 29 and 33 which show these inhibitors to prefer binding of the 3R diastereomer. The 3-amidopyrrolidin-4-one inhibitors were bound in the active site of the enzyme in two alternate directions. Epimerization issues associated with the labile alpha-amino ketone diastereomeric center contained within these inhibitor classes has proven to limit their utility despite promising pharmacokinetics displayed in both series of compounds.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/CTSK protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Cathepsin K,
http://linkedlifedata.com/resource/pubmed/chemical/Cathepsins,
http://linkedlifedata.com/resource/pubmed/chemical/Ctsk protein, rat,
http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Furans,
http://linkedlifedata.com/resource/pubmed/chemical/Ketones,
http://linkedlifedata.com/resource/pubmed/chemical/Piperidines,
http://linkedlifedata.com/resource/pubmed/chemical/Pyrans,
http://linkedlifedata.com/resource/pubmed/chemical/Pyrrolidinones
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pubmed:status |
MEDLINE
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pubmed:month |
Mar
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pubmed:issn |
0022-2623
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pubmed:author |
pubmed-author:D'AlessioKK,
pubmed-author:FenwickA EAE,
pubmed-author:GarnierBB,
pubmed-author:GribbleA DAD,
pubmed-author:HemlingM EME,
pubmed-author:JansonC ACA,
pubmed-author:LoCastroS MSM,
pubmed-author:MarquisR WRW,
pubmed-author:McQueneyM SMS,
pubmed-author:QuinnC JCJ,
pubmed-author:RL,
pubmed-author:SmithW WWW,
pubmed-author:TewDD,
pubmed-author:TomaszekTT,
pubmed-author:TroutR ERE,
pubmed-author:VeberD FDF,
pubmed-author:WitheringtonJJ,
pubmed-author:ZengJJ,
pubmed-author:ZhaoBB
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pubmed:issnType |
Print
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pubmed:day |
1
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pubmed:volume |
44
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
725-36
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pubmed:dateRevised |
2009-11-19
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pubmed:meshHeading |
pubmed-meshheading:11262083-Animals,
pubmed-meshheading:11262083-Binding Sites,
pubmed-meshheading:11262083-Cathepsin K,
pubmed-meshheading:11262083-Cathepsins,
pubmed-meshheading:11262083-Chromatography, Liquid,
pubmed-meshheading:11262083-Crystallography, X-Ray,
pubmed-meshheading:11262083-Enzyme Inhibitors,
pubmed-meshheading:11262083-Furans,
pubmed-meshheading:11262083-Humans,
pubmed-meshheading:11262083-Ketones,
pubmed-meshheading:11262083-Mass Spectrometry,
pubmed-meshheading:11262083-Models, Molecular,
pubmed-meshheading:11262083-Molecular Structure,
pubmed-meshheading:11262083-Piperidines,
pubmed-meshheading:11262083-Pyrans,
pubmed-meshheading:11262083-Pyrrolidinones,
pubmed-meshheading:11262083-Rats,
pubmed-meshheading:11262083-Stereoisomerism,
pubmed-meshheading:11262083-Structure-Activity Relationship
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pubmed:year |
2001
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pubmed:articleTitle |
Cyclic ketone inhibitors of the cysteine protease cathepsin K.
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pubmed:affiliation |
Department of Medicinal Chemistry, GlaxoSmithKline, King of Prussia, Pennsylvania 19406, USA. Robert_W_Marquis@sbphrd.com
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pubmed:publicationType |
Journal Article
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