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Bioorg Med Chem Lett. 2010 Aug 1;20(15):4507-10. doi: 10.1016/j.bmcl.2010.06.043. Epub 2010 Jun 10.

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

Author information

1
Merck Research Laboratories, MSD, Newhouse, Lanarkshire, UK. jiaqiang.cai@merck.com

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.

PMID:
20580231
DOI:
10.1016/j.bmcl.2010.06.043
[Indexed for MEDLINE]

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