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%.
Schering-Plough Corporation, Newhouse, Lanarkshire, ML1 5SH Scotland, United Kingdom. zoran.rankovic@spcorp.com
Zoran
Z
Rankovic
Jiaqiang
J
Cai
Jennifer
J
Kerr
Xavier
X
Fradera
John
J
Robinson
Ashvin
A
Mistry
Emma
E
Hamilton
George
G
McGarry
Fiona
F
Andrews
Wilson
W
Caulfield
Iain
I
Cumming
Maureen
M
Dempster
John
J
Waller
Paul
P
Scullion
Iain
I
Martin
Ann
A
Mitchell
Clive
C
Long
Mark
M
Baugh
Paul
P
Westwood
Emma
E
Kinghorn
John
J
Bruin
William
W
Hamilton
Joost
J
Uitdehaag
Mario
M
van Zeeland
Dominique
D
Potin
Laurent
L
Saniere
Andre
A
Fouquet
François
F
Chevallier
Hortense
H
Deronzier
Cecile
C
Dorleans
Eric
E
Nicolai
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