Potent and selective P2-P3 ketoamide inhibitors of cathepsin K with good pharmacokinetic properties via favorable P1', P1, and/or P3 substitutions.
A series of ketoamides were synthesized and evaluated for inhibitory activity against cathepsin K. Exploration of the interactions between achiral P(2) substituents and the cysteine protease based on molecular modelling suggestions resulted in potent cathepsin K inhibitors that demonstrated high selectivity versus cathepsins B, H, and L. Subsequent modifications of the P(3), P(1), and P(1') moieties afforded orally bioavailable inhibitors.
Barrett
David G
DG
Department of Medicinal Chemistry, GlaxoSmithKline, Research Triangle Park, NC 27709, USA.
Catalano
John G
JG
Deaton
David N
DN
Hassell
Anne M
AM
Long
Stacey T
ST
Miller
Aaron B
AB
Miller
Larry R
LR
Shewchuk
Lisa M
LM
Wells-Knecht
Kevin J
KJ
Willard
Derril H
DH
Wright
Lois L
LL
D000577:Amides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001665:Binding Sites; D056657:Cathepsin K; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis*; D006801:Humans; D013329:Structure-Activity Relationship
D000577:Amides; D015853:Cysteine Proteinase Inhibitors; D002403:Cathepsins; C534130:CTSK protein, human; D056657:Cathepsin K