Utilization of a nitrogen-sulfur nonbonding interaction in the design of new 2-aminothiazol-5-yl-pyrimidines as p38α MAP kinase inhibitors

Shuqun Lin; Stephen T. Wrobleski; John Hynes; Sidney Pitt; Rosemary Zhang; Yi Fan; Arthur M. Doweyko; Kevin F. Kish; John S. Sack; Mary F. Malley; Susan E. Kiefer; John A. Newitt; Murray McKinnon; James Trzaskos; Joel C. Barrish; John H. Dodd; Gary L. Schieven; Katerina Leftheris

doi:10.1016/j.bmcl.2010.07.102

Utilization of a nitrogen-sulfur nonbonding interaction in the design of new 2-aminothiazol-5-yl-pyrimidines as p38α MAP kinase inhibitors

Shuqun Lin, Stephen T. Wrobleski, John Hynes, Sidney Pitt, Rosemary Zhang, Yi Fan, Arthur M. Doweyko, Kevin F. Kish, John S. Sack, Mary F. Malley, Susan E. Kiefer, John A. Newitt, Murray McKinnon, James Trzaskos, Joel C. Barrish, John H. Dodd, Gary L. Schieven, Katerina Leftheris

Chemistry

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34 Scopus citations

Abstract

The design, synthesis, and structure-activity relationships (SAR) of a series of 2-aminothiazol-5-yl-pyrimidines as novel p38α MAP kinase inhibitors are described. These efforts led to the identification of 41 as a potent p38α inhibitor that utilizes a unique nitrogen-sulfur intramolecular nonbonding interaction to stabilize the conformation required for binding to the p38α active site. X-ray crystallographic studies that confirm the proposed binding mode of this class of inhibitors in p38α and provide evidence for the proposed intramolecular nitrogen-sulfur interaction are discussed.

Original language	English (US)
Pages (from-to)	5864-5868
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	20
Issue number	19
DOIs	https://doi.org/10.1016/j.bmcl.2010.07.102
State	Published - Oct 1 2010

All Science Journal Classification (ASJC) codes

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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10.1016/j.bmcl.2010.07.102

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Lin, S., Wrobleski, S. T., Hynes, J., Pitt, S., Zhang, R., Fan, Y., Doweyko, A. M., Kish, K. F., Sack, J. S., Malley, M. F., Kiefer, S. E., Newitt, J. A., McKinnon, M., Trzaskos, J., Barrish, J. C., Dodd, J. H., Schieven, G. L., & Leftheris, K. (2010). Utilization of a nitrogen-sulfur nonbonding interaction in the design of new 2-aminothiazol-5-yl-pyrimidines as p38α MAP kinase inhibitors. Bioorganic and Medicinal Chemistry Letters, 20(19), 5864-5868. https://doi.org/10.1016/j.bmcl.2010.07.102

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title = "Utilization of a nitrogen-sulfur nonbonding interaction in the design of new 2-aminothiazol-5-yl-pyrimidines as p38α MAP kinase inhibitors",

abstract = "The design, synthesis, and structure-activity relationships (SAR) of a series of 2-aminothiazol-5-yl-pyrimidines as novel p38α MAP kinase inhibitors are described. These efforts led to the identification of 41 as a potent p38α inhibitor that utilizes a unique nitrogen-sulfur intramolecular nonbonding interaction to stabilize the conformation required for binding to the p38α active site. X-ray crystallographic studies that confirm the proposed binding mode of this class of inhibitors in p38α and provide evidence for the proposed intramolecular nitrogen-sulfur interaction are discussed.",

author = "Shuqun Lin and Wrobleski, {Stephen T.} and John Hynes and Sidney Pitt and Rosemary Zhang and Yi Fan and Doweyko, {Arthur M.} and Kish, {Kevin F.} and Sack, {John S.} and Malley, {Mary F.} and Kiefer, {Susan E.} and Newitt, {John A.} and Murray McKinnon and James Trzaskos and Barrish, {Joel C.} and Dodd, {John H.} and Schieven, {Gary L.} and Katerina Leftheris",

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doi = "10.1016/j.bmcl.2010.07.102",

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Lin, S, Wrobleski, ST, Hynes, J, Pitt, S, Zhang, R, Fan, Y, Doweyko, AM, Kish, KF, Sack, JS, Malley, MF, Kiefer, SE, Newitt, JA, McKinnon, M, Trzaskos, J, Barrish, JC, Dodd, JH, Schieven, GL & Leftheris, K 2010, 'Utilization of a nitrogen-sulfur nonbonding interaction in the design of new 2-aminothiazol-5-yl-pyrimidines as p38α MAP kinase inhibitors', Bioorganic and Medicinal Chemistry Letters, vol. 20, no. 19, pp. 5864-5868. https://doi.org/10.1016/j.bmcl.2010.07.102

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T1 - Utilization of a nitrogen-sulfur nonbonding interaction in the design of new 2-aminothiazol-5-yl-pyrimidines as p38α MAP kinase inhibitors

AU - Lin, Shuqun

AU - Wrobleski, Stephen T.

AU - Hynes, John

AU - Pitt, Sidney

AU - Zhang, Rosemary

AU - Fan, Yi

AU - Doweyko, Arthur M.

AU - Kish, Kevin F.

AU - Sack, John S.

AU - Malley, Mary F.

AU - Kiefer, Susan E.

AU - Newitt, John A.

AU - McKinnon, Murray

AU - Trzaskos, James

AU - Barrish, Joel C.

AU - Dodd, John H.

AU - Schieven, Gary L.

AU - Leftheris, Katerina

PY - 2010/10/1

Y1 - 2010/10/1

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Utilization of a nitrogen-sulfur nonbonding interaction in the design of new 2-aminothiazol-5-yl-pyrimidines as p38α MAP kinase inhibitors

Abstract

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