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
Thrombin inhibitors incorporating o-aminoalkylbenzylamides in the P1 position were designed, synthesized and found to have enhanced potency and selectivity in several different structural classes. X-ray crystallographic analysis of compound 24 bound in the alpha-thrombin-hirugen complex provides an explanation for these unanticipated results.
