Pyridylthiazole-based ureas as inhibitors of Rho associated protein kinases (ROCK1 and 2)

Roberta Pireddu, Kara D. Forinash, Nan N. Sun, Mathew P. Martin, Shen Shu Sung, Brian Alexander, Jin Yi Zhu, Wayne C. Guida, Ernst Schönbrunn, Saïd M. Sebti, Nicholas J. Lawrence

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Potent ROCK inhibitors of a new class of 1-benzyl-3-(4-pyridylthiazol-2-yl) ureas have been identified. Remarkable differences in activity were observed for ureas bearing a benzylic stereogenic center. Derivatives with hydroxy, methoxy and amino groups at the meta position of the phenyl ring give rise to the most potent inhibitors (low nM). Substitutions at the para position result in substantial loss of potency. Changes at the benzylic position are tolerated resulting in significant potency in the case of methyl and methylenehydroxy groups. X-Ray crystallography was used to establish the binding mode of this class of inhibitors and provides an explanation for the observed differences of the enantiomer series. Potent inhibition of ROCK in human lung cancer cells was shown by suppression of the levels of phosphorylation of the ROCK substrate MYPT-1.

Original languageEnglish (US)
Pages (from-to)699-709
Number of pages11
JournalMedChemComm
Volume3
Issue number6
DOIs
StatePublished - Jun 2012

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rho-Associated Kinases
Protein Kinases
Urea
Bearings (structural)
Phosphorylation
Enantiomers
X ray crystallography
X Ray Crystallography
Lung Neoplasms
Substitution reactions
Cells
Derivatives
Substrates

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry

Cite this

Pireddu, R., Forinash, K. D., Sun, N. N., Martin, M. P., Sung, S. S., Alexander, B., ... Lawrence, N. J. (2012). Pyridylthiazole-based ureas as inhibitors of Rho associated protein kinases (ROCK1 and 2). MedChemComm, 3(6), 699-709. https://doi.org/10.1039/c2md00320a
Pireddu, Roberta ; Forinash, Kara D. ; Sun, Nan N. ; Martin, Mathew P. ; Sung, Shen Shu ; Alexander, Brian ; Zhu, Jin Yi ; Guida, Wayne C. ; Schönbrunn, Ernst ; Sebti, Saïd M. ; Lawrence, Nicholas J. / Pyridylthiazole-based ureas as inhibitors of Rho associated protein kinases (ROCK1 and 2). In: MedChemComm. 2012 ; Vol. 3, No. 6. pp. 699-709.
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Pireddu, R, Forinash, KD, Sun, NN, Martin, MP, Sung, SS, Alexander, B, Zhu, JY, Guida, WC, Schönbrunn, E, Sebti, SM & Lawrence, NJ 2012, 'Pyridylthiazole-based ureas as inhibitors of Rho associated protein kinases (ROCK1 and 2)', MedChemComm, vol. 3, no. 6, pp. 699-709. https://doi.org/10.1039/c2md00320a

Pyridylthiazole-based ureas as inhibitors of Rho associated protein kinases (ROCK1 and 2). / Pireddu, Roberta; Forinash, Kara D.; Sun, Nan N.; Martin, Mathew P.; Sung, Shen Shu; Alexander, Brian; Zhu, Jin Yi; Guida, Wayne C.; Schönbrunn, Ernst; Sebti, Saïd M.; Lawrence, Nicholas J.

In: MedChemComm, Vol. 3, No. 6, 06.2012, p. 699-709.

Research output: Contribution to journalArticle

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AU - Pireddu, Roberta

AU - Forinash, Kara D.

AU - Sun, Nan N.

AU - Martin, Mathew P.

AU - Sung, Shen Shu

AU - Alexander, Brian

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AU - Lawrence, Nicholas J.

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