Design and optimization of a series of novel 2-cyano-pyrimidines as cathepsin K inhibitors.
Morphing structural features of HTS-derived chemotypes led to the discovery of novel 2-cyano-pyrimidine inhibitors of cathepsin K with good pharmacokinetic profiles, for example, compound 20 showed high catK potency (IC(50)=4nM), >580-fold selectivity over catL and catB, and oral bioavailability in the rat of 52%.
Rankovic
Zoran
Z
Schering-Plough Corporation, Newhouse, Lanarkshire, ML1 5SH Scotland, United Kingdom. zoran.rankovic@spcorp.com
Cai
Jiaqiang
J
Kerr
Jennifer
J
Fradera
Xavier
X
Robinson
John
J
Mistry
Ashvin
A
Hamilton
Emma
E
McGarry
George
G
Andrews
Fiona
F
Caulfield
Wilson
W
Cumming
Iain
I
Dempster
Maureen
M
Waller
John
J
Scullion
Paul
P
Martin
Iain
I
Mitchell
Ann
A
Long
Clive
C
Baugh
Mark
M
Westwood
Paul
P
Kinghorn
Emma
E
Bruin
John
J
Hamilton
William
W
Uitdehaag
Joost
J
van Zeeland
Mario
M
Potin
Dominique
D
Saniere
Laurent
L
Fouquet
Andre
A
Chevallier
François
F
Deronzier
Hortense
H
Dorleans
Cecile
C
Nicolai
Eric
E
D000284:Administration, Oral; D000818:Animals; D001665:Binding Sites; D056657:Cathepsin K / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002460:Cell Line; D018360:Crystallography, X-Ray; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D015195:Drug Design; D057166:High-Throughput Screening Assays; D006801:Humans; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
D015853:Cysteine Proteinase Inhibitors; D011743:Pyrimidines; D056657:Cathepsin K