Enhancement of kinase selectivity in a potent class of arylamide FMS inhibitors

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

doi:10.1016/j.bmcl.2013.09.061

Enhancement of kinase selectivity in a potent class of arylamide FMS inhibitors

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

RUBRIC

Rutgers, The State University

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

3 Scopus citations

Abstract

Structure-activity relationship (SAR) studies on a highly potent series of arylamide FMS inhibitors were carried out with the aim of improving FMS kinase selectivity, particularly over KIT. Potent compound 17r (FMS IC₅₀ 0.7 nM, FMS cell IC₅₀ 6.1 nM) was discovered that had good PK properties and a greater than fivefold improvement in selectivity for FMS over KIT kinase in a cellular assay relative to the previously reported clinical candidate 4. This improved selectivity was manifested in vivo by no observed decrease in circulating reticulocytes, a measure of bone safety, at the highest studied dose. Compound 17r was highly active in a mouse pharmacodynamic model and demonstrated disease-modifying effects in a dose-dependent manner in a strep cell wall-induced arthritis model of rheumatoid arthritis in rats.

Original language	American English
Pages (from-to)	6363-6369
Number of pages	7
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	23
Issue number	23
DOIs	https://doi.org/10.1016/j.bmcl.2013.09.061
State	Published - Dec 1 2013

ASJC Scopus subject areas

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

Keywords

Anti-inflammatory
Colony-stimulating factor-1 receptor
FMS
Hypocellularity
KIT
Macrophage colony-stimulating factor
Rheumatoid arthritis

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10.1016/j.bmcl.2013.09.061

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Illig, C. R., Manthey, C. L., Meegalla, S. K., Wall, M. J., Chen, J., Wilson, K. J., Desjarlais, R. L., Ballentine, S. K., Schubert, C., Crysler, C. S., Chen, Y., Molloy, C. J., Chaikin, M. A., Donatelli, R. R., Yurkow, E., Zhou, Z., Player, M. R., & Tomczuk, B. E. (2013). Enhancement of kinase selectivity in a potent class of arylamide FMS inhibitors. Bioorganic and Medicinal Chemistry Letters, 23(23), 6363-6369. https://doi.org/10.1016/j.bmcl.2013.09.061

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title = "Enhancement of kinase selectivity in a potent class of arylamide FMS inhibitors",

abstract = "Structure-activity relationship (SAR) studies on a highly potent series of arylamide FMS inhibitors were carried out with the aim of improving FMS kinase selectivity, particularly over KIT. Potent compound 17r (FMS IC50 0.7 nM, FMS cell IC50 6.1 nM) was discovered that had good PK properties and a greater than fivefold improvement in selectivity for FMS over KIT kinase in a cellular assay relative to the previously reported clinical candidate 4. This improved selectivity was manifested in vivo by no observed decrease in circulating reticulocytes, a measure of bone safety, at the highest studied dose. Compound 17r was highly active in a mouse pharmacodynamic model and demonstrated disease-modifying effects in a dose-dependent manner in a strep cell wall-induced arthritis model of rheumatoid arthritis in rats.",

keywords = "Anti-inflammatory, Colony-stimulating factor-1 receptor, FMS, Hypocellularity, KIT, Macrophage colony-stimulating factor, Rheumatoid arthritis",

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

year = "2013",

month = dec,

day = "1",

doi = "10.1016/j.bmcl.2013.09.061",

language = "American English",

volume = "23",

pages = "6363--6369",

journal = "Bioorganic and Medicinal Chemistry Letters",

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Illig, CR, Manthey, CL, Meegalla, SK, Wall, MJ, Chen, J, Wilson, KJ, Desjarlais, RL, Ballentine, SK, Schubert, C, Crysler, CS, Chen, Y, Molloy, CJ, Chaikin, MA, Donatelli, RR, Yurkow, E, Zhou, Z, Player, MR & Tomczuk, BE 2013, 'Enhancement of kinase selectivity in a potent class of arylamide FMS inhibitors', Bioorganic and Medicinal Chemistry Letters, vol. 23, no. 23, pp. 6363-6369. https://doi.org/10.1016/j.bmcl.2013.09.061

TY - JOUR

T1 - Enhancement of kinase selectivity in a potent class of arylamide FMS inhibitors

AU - Illig, Carl R.

AU - Manthey, Carl L.

AU - Meegalla, Sanath K.

AU - Wall, Mark J.

AU - Chen, Jinsheng

AU - Wilson, Kenneth J.

AU - Desjarlais, Renee L.

AU - Ballentine, Shelley K.

AU - Schubert, Carsten

AU - Crysler, Carl S.

AU - Chen, Yanmin

AU - Molloy, Christopher J.

AU - Chaikin, Margery A.

AU - Donatelli, Robert R.

AU - Yurkow, Edward

AU - Zhou, Zhao

AU - Player, Mark R.

AU - Tomczuk, Bruce E.

PY - 2013/12/1

Y1 - 2013/12/1

N2 - Structure-activity relationship (SAR) studies on a highly potent series of arylamide FMS inhibitors were carried out with the aim of improving FMS kinase selectivity, particularly over KIT. Potent compound 17r (FMS IC50 0.7 nM, FMS cell IC50 6.1 nM) was discovered that had good PK properties and a greater than fivefold improvement in selectivity for FMS over KIT kinase in a cellular assay relative to the previously reported clinical candidate 4. This improved selectivity was manifested in vivo by no observed decrease in circulating reticulocytes, a measure of bone safety, at the highest studied dose. Compound 17r was highly active in a mouse pharmacodynamic model and demonstrated disease-modifying effects in a dose-dependent manner in a strep cell wall-induced arthritis model of rheumatoid arthritis in rats.

AB - Structure-activity relationship (SAR) studies on a highly potent series of arylamide FMS inhibitors were carried out with the aim of improving FMS kinase selectivity, particularly over KIT. Potent compound 17r (FMS IC50 0.7 nM, FMS cell IC50 6.1 nM) was discovered that had good PK properties and a greater than fivefold improvement in selectivity for FMS over KIT kinase in a cellular assay relative to the previously reported clinical candidate 4. This improved selectivity was manifested in vivo by no observed decrease in circulating reticulocytes, a measure of bone safety, at the highest studied dose. Compound 17r was highly active in a mouse pharmacodynamic model and demonstrated disease-modifying effects in a dose-dependent manner in a strep cell wall-induced arthritis model of rheumatoid arthritis in rats.

KW - Anti-inflammatory

KW - Colony-stimulating factor-1 receptor

KW - FMS

KW - Hypocellularity

KW - KIT

KW - Macrophage colony-stimulating factor

KW - Rheumatoid arthritis

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DO - 10.1016/j.bmcl.2013.09.061

M3 - Article

C2 - 24138939

SN - 0960-894X

VL - 23

SP - 6363

EP - 6369

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 23

ER -

Enhancement of kinase selectivity in a potent class of arylamide FMS inhibitors

Abstract

ASJC Scopus subject areas

Keywords

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