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.
Barrett
David G
DG
Department of Medicinal Chemistry, GlaxoSmithKline, Research Triangle Park, NC 27709, USA.
Boncek
Virginia M
VM
Catalano
John G
JG
Deaton
David N
DN
Hassell
Anne M
AM
Jurgensen
Cynthia H
CH
Long
Stacey T
ST
McFadyen
Robert B
RB
Miller
Aaron B
AB
Miller
Larry R
LR
Payne
J Alan
JA
Ray
John A
JA
Samano
Vicente
V
Shewchuk
Lisa M
LM
Tavares
Francis X
FX
Wells-Knecht
Kevin J
KJ
Willard
Derril H
DH
Wright
Lois L
LL
Zhou
Hui-Qiang Q
HQ
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