Synthesis of potential thrombin inhibitors. Incorporation of tartaric acid templates as P2 proline mimetics.
With the objective to prepare novel non-peptidic thrombin inhibitors, bioisosteres of the inhibitory tripeptide D-Phe-Pro-Arg chain have been examined. Thus, the P1 Arg was replaced with p-amidinobenzylamine, an elongated homologue of the same and with 2,5-dichloro benzylamine. The P2-P3, D-Phe-Pro, was replaced with a novel tartaric acid template coupled to a series of readily available, mainly lipophilic, amines. Some of these compounds exhibit promising thrombin inhibition activity in vitro, IC(50 ) approximately 5.9 microM.
Dahlgren
Anders
A
Department of Chemistry, Linköping University, S-581 83 Linköping, Sweden.
Brånalt
Jonas
J
Kvarnström
Ingemar
I
Nilsson
Ingemar
I
Musil
Djordje
D
Samuelsson
Bertil
B
D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000925:Anticoagulants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D006801:Humans; D020128:Inhibitory Concentration 50; D018716:Molecular Mimicry; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011392:Proline / Q000737:chemistry*; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013644:Tartrates / Q000737:chemistry*; D013917:Thrombin / Q000037:antagonists & inhibitors*
D000588:Amines; D000925:Anticoagulants; D009842:Oligopeptides; D015842:Serine Proteinase Inhibitors; D013644:Tartrates; C077952:phenylalanyl-prolyl-arginine; D011392:Proline; D013917:Thrombin; C029768:tartaric acid