title: Novel and potent cyclic cyanamide-based cathepsin K inhibitors.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, GlaxoSmithKline, Research Triangle Park, NC 27709, USA. david.n.deaton@gsk.com
authors.forename: David N
authors.initials: DN
authors.lastname: Deaton
authors.forename: Anne M
authors.initials: AM
authors.lastname: Hassell
authors.forename: Robert B
authors.initials: RB
authors.lastname: McFadyen
authors.forename: Aaron B
authors.initials: AB
authors.lastname: Miller
authors.forename: Larry R
authors.initials: LR
authors.lastname: Miller
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Shewchuk
authors.forename: Francis X
authors.initials: FX
authors.lastname: Tavares
authors.forename: Derril H
authors.initials: DH
authors.lastname: Willard
authors.forename: Lois L
authors.initials: LL
authors.lastname: Wright
mesh_terms: 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
chemical_list: D015853:Cysteine Proteinase Inhibitors; D011759:Pyrrolidines; D003484:Cyanamide; D002403:Cathepsins; D056657:Cathepsin K; C032519:pyrrolidine