Novel and potent cyclic cyanamide-based cathepsin K inhibitors.
Starting from a PDE IV inhibitor hit derived from high throughput screening of the compound collection, a key pyrrolidine cyanamide pharmacophore was identified. Modifications of the pyrrolidine ring produced enhancements in cathepsin K inhibition. An X-ray co-crystal structure of a cyanamide with cathepsin K confirmed the mode of inhibition.
Deaton
David N
DN
Department of Medicinal Chemistry, GlaxoSmithKline, Research Triangle Park, NC 27709, USA. david.n.deaton@gsk.com
Hassell
Anne M
AM
McFadyen
Robert B
RB
Miller
Aaron B
AB
Miller
Larry R
LR
Shewchuk
Lisa M
LM
Tavares
Francis X
FX
Willard
Derril H
DH
Wright
Lois L
LL
D000818:Animals; D056657:Cathepsin K; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D018360:Crystallography, X-Ray; D003484:Cyanamide / Q000737:chemistry*; D003500:Cyclization; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D011759:Pyrrolidines / Q000737:chemistry; D013329:Structure-Activity Relationship
D015853:Cysteine Proteinase Inhibitors; D011759:Pyrrolidines; D003484:Cyanamide; D002403:Cathepsins; D056657:Cathepsin K; C032519:pyrrolidine