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
Hauptverfasser:	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
Format:	Artikel
Sprache:	eng
Schlagworte:	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
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Beschreibung
Zusammenfassung:	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.
ISSN:	0960-894X 0968-0896 1464-3405 1464-3391
DOI:	10.1016/j.bmcl.2008.06.009