8-THP-DHI analogs as potent Type I dual TIE-2/VEGF-R2 receptor tyrosine kinase inhibitors

Robert L. Hudkins; Allison L. Zulli; Ted L. Underiner; Thelma S. Angeles; Lisa D. Aimone; Sheryl L. Meyer; Daniel Pauletti; Hong Chang; Elena V. Fedorov; Steven C. Almo; Alexander A. Fedorov; Bruce A. Ruggeri

doi:10.1016/j.bmcl.2010.04.021

8-THP-DHI analogs as potent Type I dual TIE-2/VEGF-R2 receptor tyrosine kinase inhibitors

Robert L. Hudkins, Allison L. Zulli, Ted L. Underiner, Thelma S. Angeles, Lisa D. Aimone, Sheryl L. Meyer, Daniel Pauletti, Hong Chang, Elena V. Fedorov, Steven C. Almo, Alexander A. Fedorov, Bruce A. Ruggeri

Biochemistry

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

11 Scopus citations

Abstract

A novel series of 8-(2-tetrahydropyranyl)-12,13-dihydroindazolo[5,4-a]pyrrolo[3,4-c]carbazoles (THP-DHI) was synthesized and evaluated as dual TIE-2 and VEGF-R2 receptor tyrosine kinase inhibitors. Development of the structure-activity relationships (SAR) with the support of X-ray crystallography led to identification of 7f and 7g as potent, selective dual TIE-2/VEGF-R2 inhibitors with excellent cellular potency and acceptable pharmacokinetic properties. Compounds 7f and 7g were orally active in tumor models with no observed toxicity.

Original language	English (US)
Pages (from-to)	3356-3360
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	20
Issue number	11
DOIs	https://doi.org/10.1016/j.bmcl.2010.04.021
State	Published - Jun 1 2010

Keywords

Angiogenesis
Kinase inhibitor
TIE-2
VEGF-R2

ASJC Scopus subject areas

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

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10.1016/j.bmcl.2010.04.021

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Hudkins, R. L., Zulli, A. L., Underiner, T. L., Angeles, T. S., Aimone, L. D., Meyer, S. L., Pauletti, D., Chang, H., Fedorov, E. V., Almo, S. C., Fedorov, A. A., & Ruggeri, B. A. (2010). 8-THP-DHI analogs as potent Type I dual TIE-2/VEGF-R2 receptor tyrosine kinase inhibitors. Bioorganic and Medicinal Chemistry Letters, 20(11), 3356-3360. https://doi.org/10.1016/j.bmcl.2010.04.021

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title = "8-THP-DHI analogs as potent Type I dual TIE-2/VEGF-R2 receptor tyrosine kinase inhibitors",

abstract = "A novel series of 8-(2-tetrahydropyranyl)-12,13-dihydroindazolo[5,4-a]pyrrolo[3,4-c]carbazoles (THP-DHI) was synthesized and evaluated as dual TIE-2 and VEGF-R2 receptor tyrosine kinase inhibitors. Development of the structure-activity relationships (SAR) with the support of X-ray crystallography led to identification of 7f and 7g as potent, selective dual TIE-2/VEGF-R2 inhibitors with excellent cellular potency and acceptable pharmacokinetic properties. Compounds 7f and 7g were orally active in tumor models with no observed toxicity.",

keywords = "Angiogenesis, Kinase inhibitor, TIE-2, VEGF-R2",

author = "Hudkins, {Robert L.} and Zulli, {Allison L.} and Underiner, {Ted L.} and Angeles, {Thelma S.} and Aimone, {Lisa D.} and Meyer, {Sheryl L.} and Daniel Pauletti and Hong Chang and Fedorov, {Elena V.} and Almo, {Steven C.} and Fedorov, {Alexander A.} and Ruggeri, {Bruce A.}",

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doi = "10.1016/j.bmcl.2010.04.021",

language = "English (US)",

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journal = "Bioorganic and Medicinal Chemistry Letters",

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T1 - 8-THP-DHI analogs as potent Type I dual TIE-2/VEGF-R2 receptor tyrosine kinase inhibitors

AU - Hudkins, Robert L.

AU - Zulli, Allison L.

AU - Underiner, Ted L.

AU - Angeles, Thelma S.

AU - Aimone, Lisa D.

AU - Meyer, Sheryl L.

AU - Pauletti, Daniel

AU - Chang, Hong

AU - Fedorov, Elena V.

AU - Almo, Steven C.

AU - Fedorov, Alexander A.

AU - Ruggeri, Bruce A.

PY - 2010/6/1

Y1 - 2010/6/1

N2 - A novel series of 8-(2-tetrahydropyranyl)-12,13-dihydroindazolo[5,4-a]pyrrolo[3,4-c]carbazoles (THP-DHI) was synthesized and evaluated as dual TIE-2 and VEGF-R2 receptor tyrosine kinase inhibitors. Development of the structure-activity relationships (SAR) with the support of X-ray crystallography led to identification of 7f and 7g as potent, selective dual TIE-2/VEGF-R2 inhibitors with excellent cellular potency and acceptable pharmacokinetic properties. Compounds 7f and 7g were orally active in tumor models with no observed toxicity.

AB - A novel series of 8-(2-tetrahydropyranyl)-12,13-dihydroindazolo[5,4-a]pyrrolo[3,4-c]carbazoles (THP-DHI) was synthesized and evaluated as dual TIE-2 and VEGF-R2 receptor tyrosine kinase inhibitors. Development of the structure-activity relationships (SAR) with the support of X-ray crystallography led to identification of 7f and 7g as potent, selective dual TIE-2/VEGF-R2 inhibitors with excellent cellular potency and acceptable pharmacokinetic properties. Compounds 7f and 7g were orally active in tumor models with no observed toxicity.

KW - Angiogenesis

KW - Kinase inhibitor

KW - TIE-2

KW - VEGF-R2

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DO - 10.1016/j.bmcl.2010.04.021

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SN - 0960-894X

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SP - 3356

EP - 3360

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 11

ER -

8-THP-DHI analogs as potent Type I dual TIE-2/VEGF-R2 receptor tyrosine kinase inhibitors

Abstract

Keywords

ASJC Scopus subject areas

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