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

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Young MB, Barrow JC, Glass KL, Lundell GF, Newton CL, Pellicore JM, Rittle KE, Selnick HG, Stauffer KJ, Vacca JP, Williams PD, Bohn D, Clayton FC, Cook JJ, Krueger JA, Kuo LC, Lewis SD, Lucas BJ, McMasters DR, Miller-Stein C, Pietrak BL, Wallace AA, White RB, Wong B, Yan Y, Nantermet PG

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

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

PubMed ID

15163182 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
D-phenylalanyl-N-(3-chlorobenzyl)-L-prolinamide	Prothrombin	Ki (nM)	250	N/A	N/A	Details