Novel, potent P2-P3 pyrrolidine derivatives of ketoamide-based cathepsin K inhibitors.
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.
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
Ray
John A
JA
Samano
Vicente
V
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; 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
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