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

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

Journal of medicinal chemistry (2004-05-28)

Mary Beth Young, James C Barrow, Kristen L Glass, George F Lundell, Christina L Newton, Janetta M Pellicore, Kenneth E Rittle, Harold G Selnick, Kenneth J Stauffer, Joseph P Vacca, Peter D Williams, Dennis Bohn, Franklin C Clayton, Jacquelynn J Cook, Julie A Krueger, Lawrence C Kuo, S Dale Lewis, Bobby J Lucas, Daniel R McMasters, Cynthia Miller-Stein, Beth L Pietrak, Audrey A Wallace, Rebecca B White, Bradley Wong, Youwei Yan, Philippe G Nantermet

PMID15163182

摘要

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.