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J Med Chem. 2004 Jun 3;47(12):2995-3008.

Discovery and evaluation of potent P1 aryl heterocycle-based thrombin inhibitors.

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Medicinal Chemistry, Merck Research Laboratories, Merck and Co., Inc., WP14-3, Post Office Box 4, Sumneytown Pike, West Point, PA 19486, USA.


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.

[Indexed for MEDLINE]

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