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.
Novartis Institutes for BioMedical Research, Ohkubo 8, Tsukuba, Ibaraki 300-2611, Japan. osamu.irie@novartis.com
Osamu
O
Irie
Takeru
T
Ehara
Atsuko
A
Iwasaki
Fumiaki
F
Yokokawa
Junichi
J
Sakaki
Hajime
H
Hirao
Takanori
T
Kanazawa
Naoki
N
Teno
Miyuki
M
Horiuchi
Ichiro
I
Umemura
Hiroki
H
Gunji
Keiichi
K
Masuya
Yuko
Y
Hitomi
Genji
G
Iwasaki
Kazuhiko
K
Nonomura
Keiko
K
Tanabe
Hiroaki
H
Fukaya
Takatoshi
T
Kosaka
Christopher R
CR
Snell
Allan
A
Hallett
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