Structure-based optimization of a potent class of arylamide FMS inhibitors

Sanath K. Meegalla; Mark J. Wall; Jinsheng Chen; Kenneth J. Wilson; Shelley K. Ballentine; Renee L. DesJarlais; Carsten Schubert; Carl S. Crysler; Yanmin Chen; Christopher J. Molloy; Margery A. Chaikin; Carl L. Manthey; Mark R. Player; Bruce E. Tomczuk; Carl R. Illig

doi:10.1016/j.bmcl.2008.04.059

Structure-based optimization of a potent class of arylamide FMS inhibitors

Sanath K. Meegalla, Mark J. Wall, Jinsheng Chen, Kenneth J. Wilson, Shelley K. Ballentine, Renee L. DesJarlais, Carsten Schubert, Carl S. Crysler, Yanmin Chen, Christopher J. Molloy, Margery A. Chaikin, Carl L. Manthey, Mark R. Player, Bruce E. Tomczuk, Carl R. Illig

Research output: Contribution to journal › Article › peer-review

33 Scopus citations

Abstract

An anti-inflammatory 1,2,4-phenylenetriamine-containing series of FMS inhibitors with a potential to form reactive metabolites was transformed into a series with equivalent potency by incorporation of carbon-based replacement groups. Structure-based modeling provided the framework to efficiently effect this transformation and restore potencies to previous levels. This optimization removed a risk factor for potential idiosyncratic drug reactions.

Original language	English (US)
Pages (from-to)	3632-3637
Number of pages	6
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	18
Issue number	12
DOIs	https://doi.org/10.1016/j.bmcl.2008.04.059
State	Published - Jun 15 2008
Externally published	Yes

All Science Journal Classification (ASJC) codes

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

Keywords

Anti-inflammatory activity
CSF-1R
Colony-stimulating factor-1
FMS
Idiosyncratic drug reactions
M-CSF
Macrophages
cFMS

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10.1016/j.bmcl.2008.04.059

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Meegalla, S. K., Wall, M. J., Chen, J., Wilson, K. J., Ballentine, S. K., DesJarlais, R. L., Schubert, C., Crysler, C. S., Chen, Y., Molloy, C. J., Chaikin, M. A., Manthey, C. L., Player, M. R., Tomczuk, B. E., & Illig, C. R. (2008). Structure-based optimization of a potent class of arylamide FMS inhibitors. Bioorganic and Medicinal Chemistry Letters, 18(12), 3632-3637. https://doi.org/10.1016/j.bmcl.2008.04.059

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abstract = "An anti-inflammatory 1,2,4-phenylenetriamine-containing series of FMS inhibitors with a potential to form reactive metabolites was transformed into a series with equivalent potency by incorporation of carbon-based replacement groups. Structure-based modeling provided the framework to efficiently effect this transformation and restore potencies to previous levels. This optimization removed a risk factor for potential idiosyncratic drug reactions.",

keywords = "Anti-inflammatory activity, CSF-1R, Colony-stimulating factor-1, FMS, Idiosyncratic drug reactions, M-CSF, Macrophages, cFMS",

author = "Meegalla, {Sanath K.} and Wall, {Mark J.} and Jinsheng Chen and Wilson, {Kenneth J.} and Ballentine, {Shelley K.} and DesJarlais, {Renee L.} and Carsten Schubert and Crysler, {Carl S.} and Yanmin Chen and Molloy, {Christopher J.} and Chaikin, {Margery A.} and Manthey, {Carl L.} and Player, {Mark R.} and Tomczuk, {Bruce E.} and Illig, {Carl R.}",

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Meegalla, SK, Wall, MJ, Chen, J, Wilson, KJ, Ballentine, SK, DesJarlais, RL, Schubert, C, Crysler, CS, Chen, Y, Molloy, CJ, Chaikin, MA, Manthey, CL, Player, MR, Tomczuk, BE & Illig, CR 2008, 'Structure-based optimization of a potent class of arylamide FMS inhibitors', Bioorganic and Medicinal Chemistry Letters, vol. 18, no. 12, pp. 3632-3637. https://doi.org/10.1016/j.bmcl.2008.04.059

TY - JOUR

T1 - Structure-based optimization of a potent class of arylamide FMS inhibitors

AU - Meegalla, Sanath K.

AU - Wall, Mark J.

AU - Chen, Jinsheng

AU - Wilson, Kenneth J.

AU - Ballentine, Shelley K.

AU - DesJarlais, Renee L.

AU - Schubert, Carsten

AU - Crysler, Carl S.

AU - Chen, Yanmin

AU - Molloy, Christopher J.

AU - Chaikin, Margery A.

AU - Manthey, Carl L.

AU - Player, Mark R.

AU - Tomczuk, Bruce E.

AU - Illig, Carl R.

PY - 2008/6/15

Y1 - 2008/6/15

N2 - An anti-inflammatory 1,2,4-phenylenetriamine-containing series of FMS inhibitors with a potential to form reactive metabolites was transformed into a series with equivalent potency by incorporation of carbon-based replacement groups. Structure-based modeling provided the framework to efficiently effect this transformation and restore potencies to previous levels. This optimization removed a risk factor for potential idiosyncratic drug reactions.

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KW - Anti-inflammatory activity

KW - CSF-1R

KW - Colony-stimulating factor-1

KW - FMS

KW - Idiosyncratic drug reactions

KW - M-CSF

KW - Macrophages

KW - cFMS

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JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 12

ER -

Structure-based optimization of a potent class of arylamide FMS inhibitors

Abstract

All Science Journal Classification (ASJC) codes

Keywords

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