Design and synthesis of tetracyclic nonpeptidic biaryl nitrile inhibitors of cathepsin K.
The synthesis and biological profile of a novel series of potent and selective inhibitors of cysteine protease cathepsin K (Cat K) are described. Pharmacokinetic evaluation of 12 indicated that some members of this series could be suitable candidates to develop new orally active therapeutic agents for the treatment of osteoporosis.
Setti
Eduardo L
EL
Celera Genomics, South San Francisco, CA 94080, USA. eduardo.setti@bcglobal.net
Venkatraman
Shankar
S
Palmer
James T
JT
Xie
Xiaoming
X
Cheung
Harry
H
Yu
Walter
W
Wesolowski
Gregg
G
Robichaud
Joel
J
D019540:Area Under Curve; D002401:Cathepsin B / Q000737:chemistry; D056657:Cathepsin K; D056668:Cathepsin L; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D002626:Chemistry, Pharmaceutical; D003546:Cysteine Endopeptidases / Q000737:chemistry; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D008958:Models, Molecular; D009570:Nitriles / Q000737:chemistry*; D010024:Osteoporosis / Q000188:drug therapy*
D004791:Enzyme Inhibitors; D009570:Nitriles; 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