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 cysteine proteases, including cathepsin K and L. Some of the inhibitors showed cellular activities in mouse splenocytes as well as oral bioavailabilities in rats.
Irie
Osamu
O
Novartis Institutes for BioMedical Research, Ohkubo 8, Tsukuba, Ibaraki 300-2611, Japan. osamu.irie@novartis.com
Ehara
Takeru
T
Iwasaki
Atsuko
A
Yokokawa
Fumiaki
F
Sakaki
Junichi
J
Hirao
Hajime
H
Kanazawa
Takanori
T
Teno
Naoki
N
Horiuchi
Miyuki
M
Umemura
Ichiro
I
Gunji
Hiroki
H
Masuya
Keiichi
K
Hitomi
Yuko
Y
Iwasaki
Genji
G
Nonomura
Kazuhiko
K
Tanabe
Keiko
K
Fukaya
Hiroaki
H
Kosaka
Takatoshi
T
Snell
Christopher R
CR
Hallett
Allan
A
D001682:Biological Availability; D056657:Cathepsin K; D056668:Cathepsin L; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D002626:Chemistry, Pharmaceutical; D003546:Cysteine Endopeptidases / Q000138:chemical synthesis* / Q000737:chemistry; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D008968:Molecular Conformation; D015394:Molecular Structure; D011725:Pyridines / Q000737:chemistry; D013329:Structure-Activity Relationship
D015853:Cysteine Proteinase Inhibitors; D011725:Pyridines; D002403:Cathepsins; D003546:Cysteine Endopeptidases; C534281:CTSL protein, human; D056668:Cathepsin L; C534278:Ctsl protein, mouse; C534280:Ctsl protein, rat; C028217:cathepsin S; C534130:CTSK protein, human; D056657:Cathepsin K; C534132:Ctsk protein, mouse; C534133:Ctsk protein, rat