6-Phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile as cathepsin S inhibitors.
6-Phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile analogues were identified as potent and selective cathepsin S inhibitor against both purified enzyme and in human JY cell based cellular assays. This core has a very stable thio-trapping nitrile war-head in comparison with the well reported pyrimidine-2-carbonitrile cysteine cathepsin inhibitors. Compound 47 is also very potent in in vivo mouse spleenic Lip10 accumulation assays.
Cai
Jiaqiang
J
Merck Research Laboratories, Newhouse, Lanarkshire ML1 5SH, UK. jiaqiang.cai@merck.com
Baugh
Mark
M
Black
Darcey
D
Long
Clive
C
Jonathan Bennett
D
D
Dempster
Maureen
M
Fradera
Xavier
X
Gillespie
Jonathan
J
Andrews
Fiona
F
Boucharens
Sylviane
S
Bruin
John
J
Cameron
Kenneth S
KS
Cumming
Iain
I
Hamilton
William
W
Jones
Philip S
PS
Kaptein
Allard
A
Kinghorn
Emma
E
Maidment
Maurice
M
Martin
Iain
I
Mitchell
Ann
A
Rankovic
Zoran
Z
Robinson
John
J
Scullion
Paul
P
Uitdehaag
Joost C M
JC
Vink
Paul
P
Westwood
Paul
P
van Zeeland
Mario
M
van Berkom
Leon
L
Bastiani
Martijn
M
Meulemans
Tommi
T
D000818:Animals; D001665:Binding Sites; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002460:Cell Line; D018360:Crystallography, X-Ray; D006801:Humans; D051379:Mice; D009570:Nitriles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship
C553244:6-phenyl-1H-imidazo(4,5-c)pyridine-4-carbonitrile; D009570:Nitriles; D011480:Protease Inhibitors; D011725:Pyridines; D002403:Cathepsins; C028217:cathepsin S