Design, synthesis, and biological evaluation of 1-phenylpyrazolo[3,4- e ]pyrrolo[3,4- G ]indolizine-4,6(1 H,5 h)-diones as new glycogen synthase kinase-3β inhibitors

Valeria La Pietra; Giuseppe La Regina; Antonio Coluccia; Valeria Famiglini; Sveva Pelliccia; Batya Plotkin; Hagit Eldar-Finkelman; Andrea Brancale; Carlo Ballatore; Alex Crowe; Kurt R. Brunden; Luciana Marinelli; Ettore Novellino; Romano Silvestri

doi:https://doi.org/10.1021/jm401466v

Design, synthesis, and biological evaluation of 1-phenylpyrazolo[3,4- e ]pyrrolo[3,4- G ]indolizine-4,6(1 H,5 h)-diones as new glycogen synthase kinase-3β inhibitors

Valeria La Pietra, Giuseppe La Regina, Antonio Coluccia, Valeria Famiglini, Sveva Pelliccia, Batya Plotkin, Hagit Eldar-Finkelman, Andrea Brancale, Carlo Ballatore, Alex Crowe, Kurt R. Brunden, Luciana Marinelli, Ettore Novellino, Romano Silvestri

Human Molecular Genetics Biochemistry

Tel Aviv University

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

Abstract

Compound 5 was selected from our in-house library as a suitable starting point for the rational design of new GSK-3β inhibitors. MC/FEP calculations of 5 led to the identication of a structural class of new GSK-3β inhibitors. Compound 18 inhibited GSK-3β with an IC₅₀ of 0.24 μM and inhibited tau phosphorylation in a cell-based assay. It proved to be a selective inhibitor of GSK-3 against a panel of 17 kinases and showed >10-fold selectivity against CDK2. Calculated physicochemical properties and Volsurf predictions suggested that compound 18 has the potential to diffuse passively across the blood-brain barrier.

Original language	English
Pages (from-to)	10066-10078
Number of pages	13
Journal	Journal of Medicinal Chemistry
Volume	56
Issue number	24
DOIs	https://doi.org/10.1021/jm401466v
State	Published - 27 Dec 2013

All Science Journal Classification (ASJC) codes

Molecular Medicine
Drug Discovery

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La Pietra, V., La Regina, G., Coluccia, A., Famiglini, V., Pelliccia, S., Plotkin, B., Eldar-Finkelman, H., Brancale, A., Ballatore, C., Crowe, A., Brunden, K. R., Marinelli, L., Novellino, E., & Silvestri, R. (2013). Design, synthesis, and biological evaluation of 1-phenylpyrazolo[3,4- e ]pyrrolo[3,4- G ]indolizine-4,6(1 H,5 h)-diones as new glycogen synthase kinase-3β inhibitors. Journal of Medicinal Chemistry, 56(24), 10066-10078. https://doi.org/10.1021/jm401466v

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title = "Design, synthesis, and biological evaluation of 1-phenylpyrazolo[3,4- e ]pyrrolo[3,4- G ]indolizine-4,6(1 H,5 h)-diones as new glycogen synthase kinase-3β inhibitors",

abstract = "Compound 5 was selected from our in-house library as a suitable starting point for the rational design of new GSK-3β inhibitors. MC/FEP calculations of 5 led to the identication of a structural class of new GSK-3β inhibitors. Compound 18 inhibited GSK-3β with an IC50 of 0.24 μM and inhibited tau phosphorylation in a cell-based assay. It proved to be a selective inhibitor of GSK-3 against a panel of 17 kinases and showed >10-fold selectivity against CDK2. Calculated physicochemical properties and Volsurf predictions suggested that compound 18 has the potential to diffuse passively across the blood-brain barrier.",

author = "{La Pietra}, Valeria and {La Regina}, Giuseppe and Antonio Coluccia and Valeria Famiglini and Sveva Pelliccia and Batya Plotkin and Hagit Eldar-Finkelman and Andrea Brancale and Carlo Ballatore and Alex Crowe and Brunden, {Kurt R.} and Luciana Marinelli and Ettore Novellino and Romano Silvestri",

year = "2013",

month = dec,

day = "27",

doi = "https://doi.org/10.1021/jm401466v",

language = "الإنجليزيّة",

volume = "56",

pages = "10066--10078",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "24",

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La Pietra, V, La Regina, G, Coluccia, A, Famiglini, V, Pelliccia, S, Plotkin, B, Eldar-Finkelman, H, Brancale, A, Ballatore, C, Crowe, A, Brunden, KR, Marinelli, L, Novellino, E & Silvestri, R 2013, 'Design, synthesis, and biological evaluation of 1-phenylpyrazolo[3,4- e ]pyrrolo[3,4- G ]indolizine-4,6(1 H,5 h)-diones as new glycogen synthase kinase-3β inhibitors', Journal of Medicinal Chemistry, vol. 56, no. 24, pp. 10066-10078. https://doi.org/10.1021/jm401466v

Design, synthesis, and biological evaluation of 1-phenylpyrazolo[3,4- e ]pyrrolo[3,4- G ]indolizine-4,6(1 H,5 h)-diones as new glycogen synthase kinase-3β inhibitors. / La Pietra, Valeria; La Regina, Giuseppe; Coluccia, Antonio et al.
In: Journal of Medicinal Chemistry, Vol. 56, No. 24, 27.12.2013, p. 10066-10078.

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

TY - JOUR

T1 - Design, synthesis, and biological evaluation of 1-phenylpyrazolo[3,4- e ]pyrrolo[3,4- G ]indolizine-4,6(1 H,5 h)-diones as new glycogen synthase kinase-3β inhibitors

AU - La Pietra, Valeria

AU - La Regina, Giuseppe

AU - Coluccia, Antonio

AU - Famiglini, Valeria

AU - Pelliccia, Sveva

AU - Plotkin, Batya

AU - Eldar-Finkelman, Hagit

AU - Brancale, Andrea

AU - Ballatore, Carlo

AU - Crowe, Alex

AU - Brunden, Kurt R.

AU - Marinelli, Luciana

AU - Novellino, Ettore

AU - Silvestri, Romano

PY - 2013/12/27

Y1 - 2013/12/27

N2 - Compound 5 was selected from our in-house library as a suitable starting point for the rational design of new GSK-3β inhibitors. MC/FEP calculations of 5 led to the identication of a structural class of new GSK-3β inhibitors. Compound 18 inhibited GSK-3β with an IC50 of 0.24 μM and inhibited tau phosphorylation in a cell-based assay. It proved to be a selective inhibitor of GSK-3 against a panel of 17 kinases and showed >10-fold selectivity against CDK2. Calculated physicochemical properties and Volsurf predictions suggested that compound 18 has the potential to diffuse passively across the blood-brain barrier.

AB - Compound 5 was selected from our in-house library as a suitable starting point for the rational design of new GSK-3β inhibitors. MC/FEP calculations of 5 led to the identication of a structural class of new GSK-3β inhibitors. Compound 18 inhibited GSK-3β with an IC50 of 0.24 μM and inhibited tau phosphorylation in a cell-based assay. It proved to be a selective inhibitor of GSK-3 against a panel of 17 kinases and showed >10-fold selectivity against CDK2. Calculated physicochemical properties and Volsurf predictions suggested that compound 18 has the potential to diffuse passively across the blood-brain barrier.

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U2 - https://doi.org/10.1021/jm401466v

DO - https://doi.org/10.1021/jm401466v

M3 - مقالة

C2 - 24295046

SN - 0022-2623

VL - 56

SP - 10066

EP - 10078

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 24

ER -

Design, synthesis, and biological evaluation of 1-phenylpyrazolo[3,4- e ]pyrrolo[3,4- G ]indolizine-4,6(1 H,5 h)-diones as new glycogen synthase kinase-3β inhibitors

Abstract

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