title: Novel, potent P2-P3 pyrrolidine derivatives of ketoamide-based cathepsin K inhibitors.
abstract: Starting from a potent pantolactone ketoamide cathepsin K inhibitor discovered from structural screening, conversion of the lactone scaffold to a pyrrolidine scaffold allowed exploration of the S(3) subsite of cathepsin K. Manipulation of P3 and P1' groups afforded potent inhibitors with drug-like properties.
authors.affiliation: Department of Medicinal Chemistry, GlaxoSmithKline, Research Triangle Park, NC 27709, USA.
authors.forename: David G
authors.initials: DG
authors.lastname: Barrett
authors.forename: John G
authors.initials: JG
authors.lastname: Catalano
authors.forename: David N
authors.initials: DN
authors.lastname: Deaton
authors.forename: Anne M
authors.initials: AM
authors.lastname: Hassell
authors.forename: Stacey T
authors.initials: ST
authors.lastname: Long
authors.forename: Aaron B
authors.initials: AB
authors.lastname: Miller
authors.forename: Larry R
authors.initials: LR
authors.lastname: Miller
authors.forename: John A
authors.initials: JA
authors.lastname: Ray
authors.forename: Vicente
authors.initials: V
authors.lastname: Samano
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Shewchuk
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Wells-Knecht
authors.forename: Derril H
authors.initials: DH
authors.lastname: Willard
authors.forename: Lois L
authors.initials: LL
authors.lastname: Wright
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D001665:Binding Sites; D056657:Cathepsin K; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D018360:Crystallography, X-Ray; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D007659:Ketones / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D015842:Serine Proteinase Inhibitors; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D015853:Cysteine Proteinase Inhibitors; D007659:Ketones; D011759:Pyrrolidines; D015842:Serine Proteinase Inhibitors; D002403:Cathepsins; C534130:CTSK protein, human; D056657:Cathepsin K; C032519:pyrrolidine