4-(3-Trifluoromethylphenyl)-pyrimidine-2-carbonitrile as cathepsin S inhibitors: N3, not N1 is critically important

…, L Popplestone, M Baugh, P Westwood, J Bruin…

Index: Cai, Jiaqiang; Fradera, Xavier; Van Zeeland, Mario; Dempster, Maureen; Cameron, Kenneth S.; Bennett, D. Jonathan; Robinson, John; Popplestone, Lucy; Baugh, Mark; Westwood, Paul; Bruin, John; Hamilton, William; Kinghorn, Emma; Long, Clive; Uitdehaag, Joost C.M. Bioorganic and Medicinal Chemistry Letters, 2010 , vol. 20, # 15 p. 4507 - 4510

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Citation Number: 13

Abstract

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 ...