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Discovery of selective and nonpeptidic cathepsin S inhibitors |
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| Authors: | 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 |
| Institution: | aNovartis Institutes for BioMedical Research, Ohkubo 8, Tsukuba, Ibaraki 300-2611, Japan;bNovartis Institutes for BioMedical Research, 5 Gower Place, London WC1E 6BS, UK |
| Abstract: | 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. |
| Keywords: | Cathepsin S inhibitor Pyrrolopyrimidine Nitrile Nonpeptidic Cysteine protease |
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