Novel pyrazinone and pyridinone thrombin inhibitors incorporating weakly basic heterobicyclic P(1)-arginine mimetics

Andreja Kranjc; Lucija Peterlin Masic; Sebastjan Reven; Klemen Mikic; Andrej Prezelj; Mojca Stegnar; Danijel Kikelj

doi:10.1016/j.ejmech.2005.03.007

Novel pyrazinone and pyridinone thrombin inhibitors incorporating weakly basic heterobicyclic P(1)-arginine mimetics

Eur J Med Chem. 2005 Aug;40(8):782-91. doi: 10.1016/j.ejmech.2005.03.007.

Authors

Andreja Kranjc¹, Lucija Peterlin Masic, Sebastjan Reven, Klemen Mikic, Andrej Prezelj, Mojca Stegnar, Danijel Kikelj

Affiliation

¹ Faculty of Pharmacy, University of Ljubljana, Askerceva 7, 1000 Ljubljana, Slovenia.

PMID: 15890436
DOI: 10.1016/j.ejmech.2005.03.007

Abstract

The design, synthesis and biological activity of new thrombin inhibitors with a pyridinone or pyrazinone core and different heterobicyclic P(1) arginine side-chain mimetics are described. The arginine side-chain mimetics used in this study are (+/-)-4,5,6,7-tetrahydro-2H-indazol-5-ylmethanamine and both enantiomers thereof, (+/-)-4,5,6,7-tetrahydro-1,3-benzothiazole-2,6-diamine and the corresponding R enantiomer. Compound 25, the most potent in the series of pyrazinone inhibitors, exhibited a K(i) of 41 nM in vitro and high selectivity against trypsin and factor Xa.

MeSH terms

Antithrombins / chemistry*
Antithrombins / pharmacology*
Arginine / chemistry*
Arginine / pharmacology*
Biomimetic Materials / chemistry
Biomimetic Materials / pharmacology*
Hydrogen-Ion Concentration
Pyrazines / chemistry*
Pyridones / chemistry*
Pyridones / therapeutic use*
Stereoisomerism

Substances

Antithrombins
Pyrazines
Pyridones
Arginine