Potent and selective cathepsin K inhibitors.
A novel series of cathepsin K inhibitors derived from Novartis compound I is described. Optimization of the P1, P3, and P1' units led to the identification of 4-aminophenoxyacetic acid 24b with an IC(50) value of 4.8 nM, which possessed an excellent selectivity over other human cathepsins and good pharmacokinetic (PK) properties. Oral administration of compound 24b to ovariectomized (OVX) rats showed a trend toward an improvement of bone mineral density (BMD) in the femur bone.
Shinozuka
Tsuyoshi
T
Medicinal Chemistry Research Laboratories, Sankyo Co., Ltd, Shinagawa-ku, Tokyo 140-8710, Japan. sinozu@sankyo.co.jp
Shimada
Kousei
K
Matsui
Satoshi
S
Yamane
Takahiro
T
Ama
Mayumi
M
Fukuda
Takeshi
T
Taki
Motohiko
M
Takeda
Yuko
Y
Otsuka
Eri
E
Yamato
Michiko
M
Mochizuki
Shin-ichi
S
Ohhata
Keiko
K
Naito
Satoru
S
D000284:Administration, Oral; D000588:Amines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D015519:Bone Density / Q000187:drug effects; D002401:Cathepsin B / Q000037:antagonists & inhibitors; D056657:Cathepsin K; D056668:Cathepsin L; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D003546:Cysteine Endopeptidases; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008099:Liver / Q000378:metabolism; D008861:Microsomes / Q000378:metabolism; D008968:Molecular Conformation; D010052:Ovariectomy; D051381:Rats; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000588:Amines; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D002403:Cathepsins; D003546:Cysteine Endopeptidases; D002401:Cathepsin B; C534281:CTSL protein, human; D056668:Cathepsin L; C534280:Ctsl protein, rat; C028217:cathepsin S; C534130:CTSK protein, human; D056657:Cathepsin K; C534133:Ctsk protein, rat