Arylamine based cathepsin K inhibitors: investigating P3 heterocyclic substituents.
A modification of novel cathepsin K inhibitors I was carried out. The structural design was aimed at reducing the lipophilic character of compounds I for obtaining better pharmacokinetic profiles. This modification afforded several less lipophilic compounds with good inhibitory activities and pharmacokinetic profiles, although the enzyme selectivity over cathepsin S was left at issue.
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
Naito
Satoru
S
D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; 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 / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008968:Molecular Conformation; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000588:Amines; D004791:Enzyme Inhibitors; D006571:Heterocyclic Compounds; D011994:Recombinant Proteins; D002403:Cathepsins; D003546:Cysteine Endopeptidases; D002401:Cathepsin B; C534281:CTSL protein, human; D056668:Cathepsin L; C028217:cathepsin S; C534130:CTSK protein, human; D056657:Cathepsin K