1sl3: Difference between revisions

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.

[[Category: Barrow, J C.]]

[[Category: Clayton, F C.]]

[[Category: Cook, J J.]]

[[Category: Glass, K L.]]

[[Category: Krueger, J A.]]

[[Category: Kuo, L C.]]

[[Category: Lewis, S D.]]

[[Category: Lucas, B J.]]

[[Category: Lundell, G F.]]

[[Category: McMasters, D R.]]

[[Category: Newton, C L.]]

[[Category: Pellicore, J M.]]

[[Category: Pietrak, B L.]]

[[Category: Rittle, K E.]]

[[Category: Selnick, H G.]]

[[Category: Stauffer, K J.]]

[[Category: Vacca, J P.]]

[[Category: Williams, P D.]]

[[Category: Young, M B.]]

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