Optimisation of the P2 pharmacophore in a series of thrombin inhibitors: ion-dipole interactions with lysine 60G.
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.
Ambler
J
J
Novartis Horsham Research Center, Horsham, West Sussex.
Brown
L
L
Cockcroft
X L
XL
Grütter
M
M
Hayler
J
J
Janus
D
D
Jones
D
D
Kane
P
P
Menear
K
K
Priestle
J
J
Smith
G
G
Talbot
M
M
Walker
C V
CV
Wathey
B
B
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
D011107:Polylysine; D011099:Polyglutamic Acid; C030391:poly(glutamic acid-lysine); D013917:Thrombin