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

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

doi:10.1021/jm030303e

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

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-SteinBeth L. Pietrak, Audrey A. Wallace, Rebecca B. White, Bradley Wong, Youwei Yan, Philippe G. Nantermet

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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 P₁ region. Various benzylamines were coupled to a pyridine/pyrazinone P₂-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 P₁ aryl heterocycles with a variety of P₂-P₃ groups produced a compound with an extraordinary thrombin inhibitory activity of 1.4 pM. It is hoped that this potency enhancement in P₁ will allow for more diversification in the P ₂-P₃ region to ultimately address additional pharmacological concerns.

Original language	English (US)
Pages (from-to)	2995-3008
Number of pages	14
Journal	Journal of medicinal chemistry
Volume	47
Issue number	12
DOIs	https://doi.org/10.1021/jm030303e
State	Published - Jun 3 2004
Externally published	Yes

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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Young, M. B., Barrow, J. C., Glass, K. L., Lundell, G. F., Newton, C. L., Pellicore, J. M., Rittle, K. E., Selnick, H. G., Stauffer, K. J., Vacca, J. P., Williams, P. D., Bohn, D., Clayton, F. C., Cook, J. J., Krueger, J. A., Kuo, L. C., Lewis, S. D., Lucas, B. J., McMasters, D. R., ... Nantermet, P. G. (2004). Discovery and evaluation of potent P₁ aryl heterocycle-based thrombin inhibitors. Journal of medicinal chemistry, 47(12), 2995-3008. https://doi.org/10.1021/jm030303e

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 2004, 'Discovery and evaluation of potent P₁ aryl heterocycle-based thrombin inhibitors', Journal of medicinal chemistry, vol. 47, no. 12, pp. 2995-3008. https://doi.org/10.1021/jm030303e

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title = "Discovery and evaluation of potent P1 aryl heterocycle-based thrombin inhibitors",

abstract = "In an effort to discover potent, clinically useful thrombin inhibitors, a rapid analogue synthetic approach was used to explore the P1 region. Various benzylamines were coupled to a pyridine/pyrazinone P2-P 3 template. One compound with an o-thiadiazole benzylic substitution was found to have a thrombin Ki 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 P1 aryl heterocycles with a variety of P2-P3 groups produced a compound with an extraordinary thrombin inhibitory activity of 1.4 pM. It is hoped that this potency enhancement in P1 will allow for more diversification in the P 2-P3 region to ultimately address additional pharmacological concerns.",

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

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AU - Pellicore, Janetta M.

AU - Rittle, Kenneth E.

AU - Selnick, Harold G.

AU - Stauffer, Kenneth J.

AU - Vacca, Joseph P.

AU - Williams, Peter D.

AU - Bohn, Dennis

AU - Clayton, Franklin C.

AU - Cook, Jacquelynn J.

AU - Krueger, Julie A.

AU - Kuo, Lawrence C.

AU - Lewis, S. Dale

AU - Lucas, Bobby J.

AU - McMasters, Daniel R.

AU - Miller-Stein, Cynthia

AU - Pietrak, Beth L.

AU - Wallace, Audrey A.

AU - White, Rebecca B.

AU - Wong, Bradley

AU - Yan, Youwei

AU - Nantermet, Philippe G.

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AB - In an effort to discover potent, clinically useful thrombin inhibitors, a rapid analogue synthetic approach was used to explore the P1 region. Various benzylamines were coupled to a pyridine/pyrazinone P2-P 3 template. One compound with an o-thiadiazole benzylic substitution was found to have a thrombin Ki 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 P1 aryl heterocycles with a variety of P2-P3 groups produced a compound with an extraordinary thrombin inhibitory activity of 1.4 pM. It is hoped that this potency enhancement in P1 will allow for more diversification in the P 2-P3 region to ultimately address additional pharmacological concerns.

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

Abstract

ASJC Scopus subject areas

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