4-(3-Trifluoromethylphenyl)-pyrimidine-2-carbonitrile as cathepsin S inhibitors: N3, not N1 is critically important |
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| Authors: | Jiaqiang Cai Xavier Fradera Mario van Zeeland Maureen Dempster Kenneth S Cameron D Jonathan Bennett John Robinson Lucy Popplestone Mark Baugh Paul Westwood John Bruin William Hamilton Emma Kinghorn Clive Long Joost CM Uitdehaag |
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| Institution: | 1. Merck Research Laboratories, MSD, Newhouse, Lanarkshire ML1 5SH, United Kingdom;2. Merck Research Laboratories, MSD, 5340BH Oss, The Netherlands |
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| 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 proposed to explain these results. |
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