Acyclic cyanamide-based inhibitors of cathepsin K.
Conversion of the proline-derived cyanamide lead to an acyclic cyanamide capable of forming an additional hydrogen bond with cathepsin K resulted in a large increase in inhibitory activity. An X-ray structure of a co-crystal of a cyanamide with cathepsin K confirmed the enzyme interaction. Furthermore, a representative acyclic cyanamide inhibitor 6r was able to attenuate bone resorption in the rat calvarial model.
Barrett
David G
DG
Department of Medicinal Chemistry, GlaxoSmithKline, Research Triangle Park, NC 27709, USA.
Deaton
David N
DN
Hassell
Anne M
AM
McFadyen
Robert B
RB
Miller
Aaron B
AB
Miller
Larry R
LR
Payne
J Alan
JA
Shewchuk
Lisa M
LM
Willard
Derril H
DH
Wright
Lois L
LL
D000818:Animals; D001665:Binding Sites; D001862:Bone Resorption; D002401:Cathepsin B / Q000037:antagonists & inhibitors; D056655:Cathepsin H; D056657:Cathepsin K; D056668:Cathepsin L; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D018360:Crystallography, X-Ray; D003484:Cyanamide / Q000737:chemistry*; D003546:Cysteine Endopeptidases; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D004195:Disease Models, Animal; D006801:Humans; D006860:Hydrogen Bonding; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D010012:Osteogenesis / Q000187:drug effects*; D011485:Protein Binding; D051381:Rats; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship
D015853:Cysteine Proteinase Inhibitors; D011994:Recombinant Proteins; D003484:Cyanamide; D002403:Cathepsins; D003546:Cysteine Endopeptidases; D002401:Cathepsin B; C534281:CTSL protein, human; D056668:Cathepsin L; C534280:Ctsl protein, rat; C534126:CTSH protein, human; D056655:Cathepsin H; C534128:Ctsh protein, rat; C534130:CTSK protein, human; D056657:Cathepsin K; C534133:Ctsk protein, rat