Optimisation of the P2 pharmacophore in a series of thrombin inhibitors: ion-dipole interactions with lysine 60G

J Ambler; L Brown; X L Cockcroft; M Grütter; J Hayler; D Janus; D Jones; P Kane; K Menear; J Priestle; G Smith; M Talbot; C V Walker; B Wathey

doi:10.1016/s0960-894x(99)00172-9

Optimisation of the P2 pharmacophore in a series of thrombin inhibitors: ion-dipole interactions with lysine 60G

Bioorg Med Chem Lett. 1999 May 3;9(9):1317-22. doi: 10.1016/s0960-894x(99)00172-9.

Authors

J Ambler¹, L Brown, X L Cockcroft, M Grütter, J Hayler, D Janus, D Jones, P Kane, K Menear, J Priestle, G Smith, M Talbot, C V Walker, B Wathey

Affiliation

¹ Novartis Horsham Research Center, Horsham, West Sussex.

PMID: 10340621
DOI: 10.1016/s0960-894x(99)00172-9

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.

MeSH terms

Crystallography, X-Ray
Humans
Kinetics
Models, Molecular
Polyglutamic Acid / analogs & derivatives*
Polyglutamic Acid / metabolism
Polylysine / analogs & derivatives*
Polylysine / metabolism
Thrombin / antagonists & inhibitors*
Thrombin / chemical synthesis*
Thrombin / pharmacokinetics

Substances

Polylysine
Polyglutamic Acid
poly(glutamic acid-lysine)
Thrombin