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
Novartis Institutes for BioMedical Research, Ohkubo 8, Tsukuba, Ibaraki 300-2611, Japan.
Bioorg Med Chem Lett. 2008 Jul 15;18(14):3959-62. doi: 10.1016/j.bmcl.2008.06.009. Epub 2008 Jun 10.
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.
非肽类、选择性且强效的组织蛋白酶S抑制剂是通过对内部吡咯并嘧啶类组织蛋白酶K抑制剂的P2和P3部分进行修饰而得到的。基于吡咯并嘧啶的抑制剂对组织蛋白酶S具有纳摩尔级别的抑制作用，对包括组织蛋白酶K和L在内的其他半胱氨酸蛋白酶具有超过100倍的选择性。其中一些抑制剂在小鼠脾细胞中表现出细胞活性，在大鼠中也具有口服生物利用度。
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