title: 4-(3-Trifluoromethylphenyl)-pyrimidine-2-carbonitrile as cathepsin S inhibitors: N3, not N1 is critically important.
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.
authors.affiliation: Merck Research Laboratories, MSD, Newhouse, Lanarkshire, UK. jiaqiang.cai@merck.com
authors.forename: Jiaqiang
authors.initials: J
authors.lastname: Cai
authors.forename: Xavier
authors.initials: X
authors.lastname: Fradera
authors.forename: Mario
authors.initials: M
authors.lastname: van Zeeland
authors.forename: Maureen
authors.initials: M
authors.lastname: Dempster
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Cameron
authors.forename: D Jonathan
authors.initials: DJ
authors.lastname: Bennett
authors.forename: John
authors.initials: J
authors.lastname: Robinson
authors.forename: Lucy
authors.initials: L
authors.lastname: Popplestone
authors.forename: Mark
authors.initials: M
authors.lastname: Baugh
authors.forename: Paul
authors.initials: P
authors.lastname: Westwood
authors.forename: John
authors.initials: J
authors.lastname: Bruin
authors.forename: William
authors.initials: W
authors.lastname: Hamilton
authors.forename: Emma
authors.initials: E
authors.lastname: Kinghorn
authors.forename: Clive
authors.initials: C
authors.lastname: Long
authors.forename: Joost C M
authors.initials: JC
authors.lastname: Uitdehaag
mesh_terms: 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*
chemical_list: D009570:Nitriles; D011480:Protease Inhibitors; D011743:Pyrimidines; D002403:Cathepsins; C028217:cathepsin S; C030986:pyrimidine