4-(3-Trifluoromethylphenyl)-pyrimidine-2-carbonitrile as cathepsin S inhibitors: N3, not N1 is critically important.
Using computer aided modelling studies, a new extended P2/S2 interaction was identified. This extended region can accommodate a variety of functional groups, such as aryls and basic amines. It was discovered that the N3 nitrogen of the pyrimidine-2-carbonitrile is critical for its cathepsin cysteine protease inhibition. N1 nitrogen also contributes to the inhibitory activity, but to a very limited degree. An 'in situ double activation' mechanism was proposed to explain these results.
Cai
Jiaqiang
J
Merck Research Laboratories, MSD, Newhouse, Lanarkshire, UK. jiaqiang.cai@merck.com
Fradera
Xavier
X
van Zeeland
Mario
M
Dempster
Maureen
M
Cameron
Kenneth S
KS
Bennett
D Jonathan
DJ
Robinson
John
J
Popplestone
Lucy
L
Baugh
Mark
M
Westwood
Paul
P
Bruin
John
J
Hamilton
William
W
Kinghorn
Emma
E
Long
Clive
C
Uitdehaag
Joost C M
JC
D001665:Binding Sites; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003198:Computer Simulation; D006801:Humans; D008958:Models, Molecular; D009570:Nitriles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011743:Pyrimidines / Q000737:chemistry*
D009570:Nitriles; D011480:Protease Inhibitors; D011743:Pyrimidines; D002403:Cathepsins; C028217:cathepsin S; C030986:pyrimidine