ABSTRACT
In an effort to discover potent, clinically useful thrombin inhibitors, a rapid analogue synthetic approach was used to explore the P(1) region. Various benzylamines were coupled to a pyridine/pyrazinone P(2)-P(3) template. One compound with an o-thiadiazole benzylic substitution was found to have a thrombin K(i) of 0.84 nM. A study of ortho-substituted five-membered-ring heterocycles was undertaken and subsequently demonstrated that the o-triazole and tetrazole rings were optimal. Combination of these potent P(1) aryl heterocycles with a variety of P(2)-P(3) groups produced a compound with an extraordinary thrombin inhibitory activity of 1.4 pM. It is hoped that this potency enhancement in P(1) will allow for more diversification in the P(2)-P(3) region to ultimately address additional pharmacological concerns.
Subject(s)
Heterocyclic Compounds/chemical synthesis , Thrombin/antagonists & inhibitors , Benzylamines/chemical synthesis , Benzylamines/chemistry , Binding Sites , Heterocyclic Compounds/chemistry , Models, Molecular , Pyrazines/chemical synthesis , Pyrazines/chemistry , Pyridines/chemical synthesis , Pyridines/chemistry , Structure-Activity Relationship , Tetrazoles/chemical synthesis , Tetrazoles/chemistry , Thiadiazoles/chemical synthesis , Thiadiazoles/chemistry , Thrombin/chemistry , Triazoles/chemical synthesis , Triazoles/chemistryABSTRACT
The synthesis and biological evaluation of a series of nonpeptidic small molecule antagonists of the human platelet thrombin receptor (PAR-1) are described. Optimization of the 5-amino-3-arylisoxazole lead resulted in an approximate 100-fold increase in potency. The most potent of these compounds (54) inhibits platelet activation with IC(50)s of 90 nM against the thrombin receptor agonist peptide (TRAP) and 510 nM against thrombin as the agonist. Further, antagonist 54 fully blocks platelet aggregation stimulated by 1 nM thrombin for 10 min.
