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 Harold Dodd, Gary L. Schieven, Katerina Leftheris

Research output: Contribution to journalArticle

25 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)5864-5868
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume20
Issue number19
DOIs
StatePublished - Oct 1 2010

Fingerprint

Pyrimidines
p38 Mitogen-Activated Protein Kinases
Sulfur
Nitrogen
Structure-Activity Relationship
Conformations
Catalytic Domain
X-Rays
X rays

All Science Journal Classification (ASJC) codes

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

Cite this

Lin, Shuqun ; Wrobleski, Stephen T. ; Hynes, John ; Pitt, Sidney ; Zhang, Rosemary ; Fan, Yi ; Doweyko, Arthur M. ; Kish, Kevin F. ; Sack, John S. ; Malley, Mary F. ; Kiefer, Susan E. ; Newitt, John A. ; McKinnon, Murray ; Trzaskos, James ; Barrish, Joel C. ; Dodd, John Harold ; Schieven, Gary L. ; Leftheris, Katerina. / Utilization of a nitrogen-sulfur nonbonding interaction in the design of new 2-aminothiazol-5-yl-pyrimidines as p38α MAP kinase inhibitors. In: Bioorganic and Medicinal Chemistry Letters. 2010 ; Vol. 20, No. 19. pp. 5864-5868.
@article{96ace60dbc28425f970ea921570be018,
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 Harold} and Schieven, {Gary L.} and Katerina Leftheris",
year = "2010",
month = "10",
day = "1",
doi = "10.1016/j.bmcl.2010.07.102",
language = "English (US)",
volume = "20",
pages = "5864--5868",
journal = "Bioorganic and Medicinal Chemistry Letters",
issn = "0960-894X",
publisher = "Elsevier Limited",
number = "19",

}

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

Utilization of a nitrogen-sulfur nonbonding interaction in the design of new 2-aminothiazol-5-yl-pyrimidines as p38α MAP kinase inhibitors. / Lin, Shuqun; Wrobleski, Stephen T.; Hynes, John; Pitt, Sidney; Zhang, Rosemary; Fan, Yi; Doweyko, Arthur M.; Kish, Kevin F.; Sack, John S.; Malley, Mary F.; Kiefer, Susan E.; Newitt, John A.; McKinnon, Murray; Trzaskos, James; Barrish, Joel C.; Dodd, John Harold; Schieven, Gary L.; Leftheris, Katerina.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 20, No. 19, 01.10.2010, p. 5864-5868.

Research output: Contribution to journalArticle

TY - JOUR

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 Harold

AU - Schieven, Gary L.

AU - Leftheris, Katerina

PY - 2010/10/1

Y1 - 2010/10/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=77957550830&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77957550830&partnerID=8YFLogxK

U2 - 10.1016/j.bmcl.2010.07.102

DO - 10.1016/j.bmcl.2010.07.102

M3 - Article

VL - 20

SP - 5864

EP - 5868

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

SN - 0960-894X

IS - 19

ER -