P2-P3 conformationally constrained ketoamide-based inhibitors of cathepsin K.
An orally bioavailable series of ketoamide-based cathepsin K inhibitors with good pharmacokinetic properties has been identified. Starting from a potent inhibitor endowed with poor drug properties, conformational constraint of the P(2)-P(3) linker and modifications to P(1') elements led to an enhancement in potency, solubility, clearance, and bioavailability. These optimized inhibitors attenuated bone resorption in a rat TPTX hypocalcemic bone resorption model.
Department of Medicinal Chemistry, GlaxoSmithKline, Research Triangle Park, NC 27709, USA.
David G
DG
Barrett
Virginia M
VM
Boncek
John G
JG
Catalano
David N
DN
Deaton
Anne M
AM
Hassell
Cynthia H
CH
Jurgensen
Stacey T
ST
Long
Robert B
RB
McFadyen
Aaron B
AB
Miller
Larry R
LR
Miller
J Alan
JA
Payne
John A
JA
Ray
Vicente
V
Samano
Lisa M
LM
Shewchuk
Francis X
FX
Tavares
Kevin J
KJ
Wells-Knecht
Derril H
DH
Willard
Lois L
LL
Wright
Hui-Qiang Q
HQ
Zhou
D000577:Amides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D001682:Biological Availability; D001862:Bone Resorption / Q000188:drug therapy / Q000378:metabolism; D056657:Cathepsin K; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D004195:Disease Models, Animal; D006996:Hypocalcemia / Q000188:drug therapy / Q000378:metabolism; D007659:Ketones / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D013329:Structure-Activity Relationship
D000577:Amides; D015853:Cysteine Proteinase Inhibitors; D007659:Ketones; D002403:Cathepsins; D056657:Cathepsin K; C534133:Ctsk protein, rat