Novel tricyclic inhibitors of 1κB kinase

James Kempson, Steven H. Spergel, Junqing Guo, Claude Quesnelle, Patrice Gill, Dominique Belanger, Alaric J. Dyckman, Tianle Li, Scott H. Watterson, Charles M. Langevine, Jagabandhu Das, Robert V. Moquin, Joseph A. Furch, Anne Marinier, Marco Dodier, Alain Martel, David Nirschl, Katy Van Kirk, James R. Burke, Mark A. PattoliKathleen Gillooly, Kim W. McIntyre, Chen Laishun, Yang Zheng, Punit H. Marathe, David Wang-Iverson, John Harold Dodd, Murray McKinnon, Joel C. Barrish, William J. Pitts

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

The design and synthesis of a novel series of oxazole-, thiazole-, and imidazole-based inhibitors of IκB kinase (IKK) are reported. Biological activity was improved compared to the pyrazolopurine lead, and the expedient synthesis of the new tricyclic systems allowed for efficient exploration of structure-activity relationships. This, combined with an iterative rat cassette dosing strategy, was used to identify compounds with improved pharmacokinetic (PK) profiles to advance for in vivo evaluation.

Original languageEnglish (US)
Pages (from-to)1994-2005
Number of pages12
JournalJournal of Medicinal Chemistry
Volume52
Issue number7
DOIs
StatePublished - Apr 9 2009

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Oxazoles
Thiazoles
Structure-Activity Relationship
Phosphotransferases
Pharmacokinetics
imidazole
Lead

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

Kempson, J., Spergel, S. H., Guo, J., Quesnelle, C., Gill, P., Belanger, D., ... Pitts, W. J. (2009). Novel tricyclic inhibitors of 1κB kinase. Journal of Medicinal Chemistry, 52(7), 1994-2005. https://doi.org/10.1021/jm8015816
Kempson, James ; Spergel, Steven H. ; Guo, Junqing ; Quesnelle, Claude ; Gill, Patrice ; Belanger, Dominique ; Dyckman, Alaric J. ; Li, Tianle ; Watterson, Scott H. ; Langevine, Charles M. ; Das, Jagabandhu ; Moquin, Robert V. ; Furch, Joseph A. ; Marinier, Anne ; Dodier, Marco ; Martel, Alain ; Nirschl, David ; Van Kirk, Katy ; Burke, James R. ; Pattoli, Mark A. ; Gillooly, Kathleen ; McIntyre, Kim W. ; Laishun, Chen ; Zheng, Yang ; Marathe, Punit H. ; Wang-Iverson, David ; Dodd, John Harold ; McKinnon, Murray ; Barrish, Joel C. ; Pitts, William J. / Novel tricyclic inhibitors of 1κB kinase. In: Journal of Medicinal Chemistry. 2009 ; Vol. 52, No. 7. pp. 1994-2005.
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author = "James Kempson and Spergel, {Steven H.} and Junqing Guo and Claude Quesnelle and Patrice Gill and Dominique Belanger and Dyckman, {Alaric J.} and Tianle Li and Watterson, {Scott H.} and Langevine, {Charles M.} and Jagabandhu Das and Moquin, {Robert V.} and Furch, {Joseph A.} and Anne Marinier and Marco Dodier and Alain Martel and David Nirschl and {Van Kirk}, Katy and Burke, {James R.} and Pattoli, {Mark A.} and Kathleen Gillooly and McIntyre, {Kim W.} and Chen Laishun and Yang Zheng and Marathe, {Punit H.} and David Wang-Iverson and Dodd, {John Harold} and Murray McKinnon and Barrish, {Joel C.} and Pitts, {William J.}",
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Kempson, J, Spergel, SH, Guo, J, Quesnelle, C, Gill, P, Belanger, D, Dyckman, AJ, Li, T, Watterson, SH, Langevine, CM, Das, J, Moquin, RV, Furch, JA, Marinier, A, Dodier, M, Martel, A, Nirschl, D, Van Kirk, K, Burke, JR, Pattoli, MA, Gillooly, K, McIntyre, KW, Laishun, C, Zheng, Y, Marathe, PH, Wang-Iverson, D, Dodd, JH, McKinnon, M, Barrish, JC & Pitts, WJ 2009, 'Novel tricyclic inhibitors of 1κB kinase', Journal of Medicinal Chemistry, vol. 52, no. 7, pp. 1994-2005. https://doi.org/10.1021/jm8015816

Novel tricyclic inhibitors of 1κB kinase. / Kempson, James; Spergel, Steven H.; Guo, Junqing; Quesnelle, Claude; Gill, Patrice; Belanger, Dominique; Dyckman, Alaric J.; Li, Tianle; Watterson, Scott H.; Langevine, Charles M.; Das, Jagabandhu; Moquin, Robert V.; Furch, Joseph A.; Marinier, Anne; Dodier, Marco; Martel, Alain; Nirschl, David; Van Kirk, Katy; Burke, James R.; Pattoli, Mark A.; Gillooly, Kathleen; McIntyre, Kim W.; Laishun, Chen; Zheng, Yang; Marathe, Punit H.; Wang-Iverson, David; Dodd, John Harold; McKinnon, Murray; Barrish, Joel C.; Pitts, William J.

In: Journal of Medicinal Chemistry, Vol. 52, No. 7, 09.04.2009, p. 1994-2005.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Novel tricyclic inhibitors of 1κB kinase

AU - Kempson, James

AU - Spergel, Steven H.

AU - Guo, Junqing

AU - Quesnelle, Claude

AU - Gill, Patrice

AU - Belanger, Dominique

AU - Dyckman, Alaric J.

AU - Li, Tianle

AU - Watterson, Scott H.

AU - Langevine, Charles M.

AU - Das, Jagabandhu

AU - Moquin, Robert V.

AU - Furch, Joseph A.

AU - Marinier, Anne

AU - Dodier, Marco

AU - Martel, Alain

AU - Nirschl, David

AU - Van Kirk, Katy

AU - Burke, James R.

AU - Pattoli, Mark A.

AU - Gillooly, Kathleen

AU - McIntyre, Kim W.

AU - Laishun, Chen

AU - Zheng, Yang

AU - Marathe, Punit H.

AU - Wang-Iverson, David

AU - Dodd, John Harold

AU - McKinnon, Murray

AU - Barrish, Joel C.

AU - Pitts, William J.

PY - 2009/4/9

Y1 - 2009/4/9

N2 - The design and synthesis of a novel series of oxazole-, thiazole-, and imidazole-based inhibitors of IκB kinase (IKK) are reported. Biological activity was improved compared to the pyrazolopurine lead, and the expedient synthesis of the new tricyclic systems allowed for efficient exploration of structure-activity relationships. This, combined with an iterative rat cassette dosing strategy, was used to identify compounds with improved pharmacokinetic (PK) profiles to advance for in vivo evaluation.

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JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

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Kempson J, Spergel SH, Guo J, Quesnelle C, Gill P, Belanger D et al. Novel tricyclic inhibitors of 1κB kinase. Journal of Medicinal Chemistry. 2009 Apr 9;52(7):1994-2005. https://doi.org/10.1021/jm8015816