| pubmed-article:11262083 | rdf:type | pubmed:Citation | lld:pubmed |
| pubmed-article:11262083 | lifeskim:mentions | umls-concept:C0284930 | lld:lifeskim |
| pubmed-article:11262083 | lifeskim:mentions | umls-concept:C2717970 | lld:lifeskim |
| pubmed-article:11262083 | lifeskim:mentions | umls-concept:C0243077 | lld:lifeskim |
| pubmed-article:11262083 | lifeskim:mentions | umls-concept:C0576783 | lld:lifeskim |
| pubmed-article:11262083 | pubmed:issue | 5 | lld:pubmed |
| pubmed-article:11262083 | pubmed:dateCreated | 2001-3-23 | lld:pubmed |
| pubmed-article:11262083 | 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. | lld:pubmed |
| pubmed-article:11262083 | pubmed:language | eng | lld:pubmed |
| pubmed-article:11262083 | pubmed:journal | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:11262083 | pubmed:citationSubset | IM | lld:pubmed |
| pubmed-article:11262083 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:11262083 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:11262083 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:11262083 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:11262083 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:11262083 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:11262083 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:11262083 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:11262083 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:11262083 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:11262083 | pubmed:status | MEDLINE | lld:pubmed |
| pubmed-article:11262083 | pubmed:month | Mar | lld:pubmed |
| pubmed-article:11262083 | pubmed:issn | 0022-2623 | lld:pubmed |
| pubmed-article:11262083 | pubmed:author | pubmed-author:VeberD FDF | lld:pubmed |
| pubmed-article:11262083 | pubmed:author | pubmed-author:JansonC ACA | lld:pubmed |
| pubmed-article:11262083 | pubmed:author | pubmed-author:SmithW WWW | lld:pubmed |
| pubmed-article:11262083 | pubmed:author | pubmed-author:GarnierBB | lld:pubmed |
| pubmed-article:11262083 | pubmed:author | pubmed-author:ZhaoBB | lld:pubmed |
| pubmed-article:11262083 | pubmed:author | pubmed-author:ZengJJ | lld:pubmed |
| pubmed-article:11262083 | pubmed:author | pubmed-author:HemlingM EME | lld:pubmed |
| pubmed-article:11262083 | pubmed:author | pubmed-author:RL | lld:pubmed |
| pubmed-article:11262083 | pubmed:author | pubmed-author:McQueneyM SMS | lld:pubmed |
| pubmed-article:11262083 | pubmed:author | pubmed-author:FenwickA EAE | lld:pubmed |
| pubmed-article:11262083 | pubmed:author | pubmed-author:TewDD | lld:pubmed |
| pubmed-article:11262083 | pubmed:author | pubmed-author:MarquisR WRW | lld:pubmed |
| pubmed-article:11262083 | pubmed:author | pubmed-author:QuinnC JCJ | lld:pubmed |
| pubmed-article:11262083 | pubmed:author | pubmed-author:GribbleA DAD | lld:pubmed |
| pubmed-article:11262083 | pubmed:author | pubmed-author:D'AlessioKK | lld:pubmed |
| pubmed-article:11262083 | pubmed:author | pubmed-author:TomaszekTT | lld:pubmed |
| pubmed-article:11262083 | pubmed:author | pubmed-author:LoCastroS MSM | lld:pubmed |
| pubmed-article:11262083 | pubmed:author | pubmed-author:WitheringtonJ... | lld:pubmed |
| pubmed-article:11262083 | pubmed:author | pubmed-author:TroutR ERE | lld:pubmed |
| pubmed-article:11262083 | pubmed:issnType | Print | lld:pubmed |
| pubmed-article:11262083 | pubmed:day | 1 | lld:pubmed |
| pubmed-article:11262083 | pubmed:volume | 44 | lld:pubmed |
| pubmed-article:11262083 | pubmed:owner | NLM | lld:pubmed |
| pubmed-article:11262083 | pubmed:authorsComplete | Y | lld:pubmed |
| pubmed-article:11262083 | pubmed:pagination | 725-36 | lld:pubmed |
| pubmed-article:11262083 | pubmed:dateRevised | 2009-11-19 | lld:pubmed |
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| pubmed-article:11262083 | pubmed:meshHeading | pubmed-meshheading:11262083... | lld:pubmed |
| pubmed-article:11262083 | pubmed:year | 2001 | lld:pubmed |
| pubmed-article:11262083 | pubmed:articleTitle | Cyclic ketone inhibitors of the cysteine protease cathepsin K. | lld:pubmed |
| pubmed-article:11262083 | pubmed:affiliation | Department of Medicinal Chemistry, GlaxoSmithKline, King of Prussia, Pennsylvania 19406, USA. Robert_W_Marquis@sbphrd.com | lld:pubmed |
| pubmed-article:11262083 | pubmed:publicationType | Journal Article | lld:pubmed |
| http://linkedlifedata.com/r... | http://linkedlifedata.com/r... | pubmed-article:11262083 | lld:chembl |
