title: Optimisation of the P2 pharmacophore in a series of thrombin inhibitors: ion-dipole interactions with lysine 60G.
abstract: The optimisation of the P2 pharmacophore in a series of thrombin inhibitors is described. The interaction of a number of piperidine P2 functionalities with lysine 60G of thrombin is explored with reference to the crystal structure of inhibitor enzyme complexes. A primary ion-dipole interaction between the terminal P2 side chain group and lysine 60G is evoked to explain the SAR in this series.
authors.affiliation: Novartis Horsham Research Center, Horsham, West Sussex.
authors.forename: J
authors.initials: J
authors.lastname: Ambler
authors.forename: L
authors.initials: L
authors.lastname: Brown
authors.forename: X L
authors.initials: XL
authors.lastname: Cockcroft
authors.forename: M
authors.initials: M
authors.lastname: Grütter
authors.forename: J
authors.initials: J
authors.lastname: Hayler
authors.forename: D
authors.initials: D
authors.lastname: Janus
authors.forename: D
authors.initials: D
authors.lastname: Jones
authors.forename: P
authors.initials: P
authors.lastname: Kane
authors.forename: K
authors.initials: K
authors.lastname: Menear
authors.forename: J
authors.initials: J
authors.lastname: Priestle
authors.forename: G
authors.initials: G
authors.lastname: Smith
authors.forename: M
authors.initials: M
authors.lastname: Talbot
authors.forename: C V
authors.initials: CV
authors.lastname: Walker
authors.forename: B
authors.initials: B
authors.lastname: Wathey
mesh_terms: D018360:Crystallography, X-Ray; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D011099:Polyglutamic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D011107:Polylysine / Q000031:analogs & derivatives* / Q000378:metabolism; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000138:chemical synthesis* / Q000493:pharmacokinetics
chemical_list: D011107:Polylysine; D011099:Polyglutamic Acid; C030391:poly(glutamic acid-lysine); D013917:Thrombin