Effect of novel N-cyano-tetrahydro-pyridazine compounds, a class of cathepsin K inhibitors, on the bone resorptive activity of mature osteoclasts.
Cathepsin K is the key regulator in the osteoclast-mediated bone resorption. Here, we found the correlation between the inhibitory activities of carbonitrile derivatives in the enzymatic activity of cathepsin K and their binding scores predicted using FlexX-Pharm docking program. The binding pattern of [1-(2-cyano-tetrahydro-pyridazine-1-carbonyl)-2-methy-propyl]-carbamic acid benzyl ester (8), one member of this series, was similar to that of the reference. In a bone pit formation assay, compound 8 was shown to dose-dependently inhibit the bone resorptive activity of mature osteoclasts.
Laboratory of Chemical Genomics, Korea Research Institute of Chemical Technology, PO Box 107, Yuseong-gu, Daejeon 305-600, Republic of Korea.
Seong Hwan
SH
Kim
Dong Joo
DJ
Jhon
Jong Hwan
JH
Song
Jae Sung
JS
No
Nam Sook
NS
Kang
D000818:Animals; D001665:Binding Sites; D001862:Bone Resorption; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism; D056657:Cathepsin K; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D002626:Chemistry, Pharmaceutical / Q000379:methods; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D051379:Mice; D008956:Models, Chemical; D010006:Osteoblasts / Q000187:drug effects*; D010010:Osteoclasts / Q000187:drug effects*; D011724:Pyridazines / Q000138:chemical synthesis* / Q000494:pharmacology
D008024:Ligands; D011724:Pyridazines; D002403:Cathepsins; C534130:CTSK protein, human; D056657:Cathepsin K; C534132:Ctsk protein, mouse