Novel pyrazinone and pyridinone thrombin inhibitors incorporating weakly basic heterobicyclic P(1)-arginine mimetics.
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.
Kranjc
Andreja
A
Faculty of Pharmacy, University of Ljubljana, Askerceva 7, 1000 Ljubljana, Slovenia.
Masic
Lucija Peterlin
LP
Reven
Sebastjan
S
Mikic
Klemen
K
Prezelj
Andrej
A
Stegnar
Mojca
M
Kikelj
Danijel
D
D000991:Antithrombins / Q000737:chemistry* / Q000494:pharmacology*; D001120:Arginine / Q000737:chemistry* / Q000494:pharmacology*; D040761:Biomimetic Materials / Q000737:chemistry / Q000494:pharmacology*; D006863:Hydrogen-Ion Concentration; D011719:Pyrazines / Q000737:chemistry*; D011728:Pyridones / Q000737:chemistry* / Q000627:therapeutic use*; D013237:Stereoisomerism
D000991:Antithrombins; D011719:Pyrazines; D011728:Pyridones; D001120:Arginine