Discovery of selective and nonpeptidic cathepsin S inhibitors
Nonpeptidic, selective, and potent cathepsin S inhibitors were derived from an in-house pyrrolopyrimidine cathepsin K inhibitor by modification of the P2 and P3 moieties. The pyrrolopyrimidine-based inhibitors show nanomolar inhibition of cathepsin S with over 100-fold selectivity against other cyst...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry 2008-07, Vol.18 (14), p.3959-3962 |
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| container_title | Bioorganic & medicinal chemistry |
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| creator | Irie, Osamu Ehara, Takeru Iwasaki, Atsuko Yokokawa, Fumiaki Sakaki, Junichi Hirao, Hajime Kanazawa, Takanori Teno, Naoki Horiuchi, Miyuki Umemura, Ichiro Gunji, Hiroki Masuya, Keiichi Hitomi, Yuko Iwasaki, Genji Nonomura, Kazuhiko Tanabe, Keiko Fukaya, Hiroaki Kosaka, Takatoshi Snell, Christopher R. Hallett, Allan |
| description | Nonpeptidic, selective, and potent cathepsin S inhibitors were derived from an in-house pyrrolopyrimidine cathepsin K inhibitor by modification of the P2 and P3 moieties. The pyrrolopyrimidine-based inhibitors show nanomolar inhibition of cathepsin S with over 100-fold selectivity against other cysteine proteases, including cathepsin K and L. Some of the inhibitors showed cellular activities in mouse splenocytes as well as oral bioavailabilities in rats. |
| doi_str_mv | 10.1016/j.bmcl.2008.06.009 |
| format | Article |
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The pyrrolopyrimidine-based inhibitors show nanomolar inhibition of cathepsin S with over 100-fold selectivity against other cysteine proteases, including cathepsin K and L. Some of the inhibitors showed cellular activities in mouse splenocytes as well as oral bioavailabilities in rats.</description><identifier>ISSN: 0960-894X</identifier><identifier>ISSN: 0968-0896</identifier><identifier>EISSN: 1464-3405</identifier><identifier>EISSN: 1464-3391</identifier><identifier>DOI: 10.1016/j.bmcl.2008.06.009</identifier><identifier>PMID: 18572405</identifier><language>eng</language><publisher>Oxford: Elsevier Ltd</publisher><subject>Biological and medical sciences ; Biological Availability ; Cathepsin K ; Cathepsin L ; Cathepsin S inhibitor ; Cathepsins - antagonists & inhibitors ; Cathepsins - chemistry ; Chemistry, Pharmaceutical ; Cysteine Endopeptidases - chemical synthesis ; Cysteine Endopeptidases - chemistry ; Cysteine protease ; Cysteine Proteinase Inhibitors - chemical synthesis ; Cysteine Proteinase Inhibitors - pharmacology ; Drug Design ; Humans ; Inhibitory Concentration 50 ; Medical sciences ; Miscellaneous ; Models, Chemical ; Molecular Conformation ; Molecular Structure ; Nitrile ; Nonpeptidic ; Pharmacology. 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The pyrrolopyrimidine-based inhibitors show nanomolar inhibition of cathepsin S with over 100-fold selectivity against other cysteine proteases, including cathepsin K and L. Some of the inhibitors showed cellular activities in mouse splenocytes as well as oral bioavailabilities in rats.</description><subject>Biological and medical sciences</subject><subject>Biological Availability</subject><subject>Cathepsin K</subject><subject>Cathepsin L</subject><subject>Cathepsin S inhibitor</subject><subject>Cathepsins - antagonists & inhibitors</subject><subject>Cathepsins - chemistry</subject><subject>Chemistry, Pharmaceutical</subject><subject>Cysteine Endopeptidases - chemical synthesis</subject><subject>Cysteine Endopeptidases - chemistry</subject><subject>Cysteine protease</subject><subject>Cysteine Proteinase Inhibitors - chemical synthesis</subject><subject>Cysteine Proteinase Inhibitors - pharmacology</subject><subject>Drug Design</subject><subject>Humans</subject><subject>Inhibitory Concentration 50</subject><subject>Medical sciences</subject><subject>Miscellaneous</subject><subject>Models, Chemical</subject><subject>Molecular Conformation</subject><subject>Molecular Structure</subject><subject>Nitrile</subject><subject>Nonpeptidic</subject><subject>Pharmacology. 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The pyrrolopyrimidine-based inhibitors show nanomolar inhibition of cathepsin S with over 100-fold selectivity against other cysteine proteases, including cathepsin K and L. Some of the inhibitors showed cellular activities in mouse splenocytes as well as oral bioavailabilities in rats.</abstract><cop>Oxford</cop><pub>Elsevier Ltd</pub><pmid>18572405</pmid><doi>10.1016/j.bmcl.2008.06.009</doi><tpages>4</tpages></addata></record> |
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| identifier | ISSN: 0960-894X |
| ispartof | Bioorganic & medicinal chemistry, 2008-07, Vol.18 (14), p.3959-3962 |
| issn | 0960-894X 0968-0896 1464-3405 1464-3391 |
| language | eng |
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| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Biological and medical sciences Biological Availability Cathepsin K Cathepsin L Cathepsin S inhibitor Cathepsins - antagonists & inhibitors Cathepsins - chemistry Chemistry, Pharmaceutical Cysteine Endopeptidases - chemical synthesis Cysteine Endopeptidases - chemistry Cysteine protease Cysteine Proteinase Inhibitors - chemical synthesis Cysteine Proteinase Inhibitors - pharmacology Drug Design Humans Inhibitory Concentration 50 Medical sciences Miscellaneous Models, Chemical Molecular Conformation Molecular Structure Nitrile Nonpeptidic Pharmacology. Drug treatments Pyridines - chemistry Pyrrolopyrimidine Structure-Activity Relationship |
| title | Discovery of selective and nonpeptidic cathepsin S inhibitors |
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