New insights into the structure-activity-relationship of selective excitatory amino acid transporter subtype 1 (EAAT1) inhibitors UCPH-101 and UCPH-102

Stinne Wessel Hansen; Mette Norman Erichsen; T.H.V. Huynh; J.A. Ruiz; Isabell Haym; Walden Emil Bjørn-Yoshimoto; Bjarke Abrahamsen; J. Hansen; M. Storgaard; A.L. Eriksen; Anders A. Jensen; Lennart Bunch

doi:10.1002/cmdc.201500525

New insights into the structure-activity-relationship of selective excitatory amino acid transporter subtype 1 (EAAT1) inhibitors UCPH-101 and UCPH-102

Stinne Wessel Hansen, Mette Norman Erichsen, T.H.V. Huynh, J.A. Ruiz, Isabell Haym, Walden Emil Bjørn-Yoshimoto, Bjarke Abrahamsen, J. Hansen, M. Storgaard, A.L. Eriksen, Anders A. Jensen, Lennart Bunch

4 Citations (Scopus)

Abstract

In the present study, we made further investigations on the structure-activity requirements of the selective excitatory amino acid transporter 1 (EAAT1) inhibitor, 2-amino-4-(4-methoxyphenyl)-7-(naphthalen-1-yl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (UCPH-101), by exploring 15 different substituents (R¹) at the 7-position in combination with eight different substituents (R²) at the 4-position. Among the 63 new analogues synthesized, we identified a number of compounds that unexpectedly displayed inhibitory activities at EAAT1 in light of understanding the structure-activity relationship (SAR) of this inhibitor class extracted from previous studies. Moreover, the nature of the R¹ and R² substituents were observed to contribute to the functional properties of the various analogues in additive and non-additive ways. Finally, separation of the four stereoisomers of analogue 14 g (2-amino-4-([1,1′-biphenyl]-4-yl)-3-cyano-7-isopropyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene) was carried out, and in agreement with a study of a related scaffold, the R configuration at C4 was found to be mandatory for inhibitory activity, while both the C7 diastereomers were found to be active as EAAT1 inhibitors. A study of the stereochemical stability of the four pure stereoisomers 14 g-A-D showed that epimerization takes places at C7 via a ring-opening, C-C bond rotation, ring-closing mechanism. Inhibition of glutamate uptake: 63 new analogues of the selective EAAT1 inhibitor UCPH-101 were synthesized and characterized pharmacologically. Analogues that unexpectedly displayed inhibitory activities at EAAT1 were identified. Furthermore, separation of the four stereoisomers of analogue 14 g revealed that, in agreement with a study of a related scaffold, the R configuration at C4 is mandatory for inhibitory activity, whereas both C7 diastereomers are active as EAAT1 inhibitors.

Original language	English
Journal	ChemMedChem
Volume	11
Pages (from-to)	382-402
Number of pages	21
ISSN	1860-7179
DOIs	https://doi.org/10.1002/cmdc.201500525
Publication status	Published - 17 Feb 2016

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Hansen, S. W., Erichsen, M. N., Huynh, T. H. V., Ruiz, J. A., Haym, I., Bjørn-Yoshimoto, W. E., Abrahamsen, B., Hansen, J., Storgaard, M., Eriksen, A. L., Jensen, A. A., & Bunch, L. (2016). New insights into the structure-activity-relationship of selective excitatory amino acid transporter subtype 1 (EAAT1) inhibitors UCPH-101 and UCPH-102. ChemMedChem, 11, 382-402. https://doi.org/10.1002/cmdc.201500525

Hansen, SW, Erichsen, MN, Huynh, THV, Ruiz, JA, Haym, I, Bjørn-Yoshimoto, WE, Abrahamsen, B, Hansen, J, Storgaard, M, Eriksen, AL, Jensen, AA & Bunch, L 2016, 'New insights into the structure-activity-relationship of selective excitatory amino acid transporter subtype 1 (EAAT1) inhibitors UCPH-101 and UCPH-102', ChemMedChem, vol. 11, pp. 382-402. https://doi.org/10.1002/cmdc.201500525

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title = "New insights into the structure-activity-relationship of selective excitatory amino acid transporter subtype 1 (EAAT1) inhibitors UCPH-101 and UCPH-102",

abstract = "In the present study, we made further investigations on the structure-activity requirements of the selective excitatory amino acid transporter 1 (EAAT1) inhibitor, 2-amino-4-(4-methoxyphenyl)-7-(naphthalen-1-yl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (UCPH-101), by exploring 15 different substituents (R1) at the 7-position in combination with eight different substituents (R2) at the 4-position. Among the 63 new analogues synthesized, we identified a number of compounds that unexpectedly displayed inhibitory activities at EAAT1 in light of understanding the structure-activity relationship (SAR) of this inhibitor class extracted from previous studies. Moreover, the nature of the R1 and R2 substituents were observed to contribute to the functional properties of the various analogues in additive and non-additive ways. Finally, separation of the four stereoisomers of analogue 14 g (2-amino-4-([1,1′-biphenyl]-4-yl)-3-cyano-7-isopropyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene) was carried out, and in agreement with a study of a related scaffold, the R configuration at C4 was found to be mandatory for inhibitory activity, while both the C7 diastereomers were found to be active as EAAT1 inhibitors. A study of the stereochemical stability of the four pure stereoisomers 14 g-A-D showed that epimerization takes places at C7 via a ring-opening, C-C bond rotation, ring-closing mechanism. Inhibition of glutamate uptake: 63 new analogues of the selective EAAT1 inhibitor UCPH-101 were synthesized and characterized pharmacologically. Analogues that unexpectedly displayed inhibitory activities at EAAT1 were identified. Furthermore, separation of the four stereoisomers of analogue 14 g revealed that, in agreement with a study of a related scaffold, the R configuration at C4 is mandatory for inhibitory activity, whereas both C7 diastereomers are active as EAAT1 inhibitors.",

author = "Hansen, {Stinne Wessel} and Erichsen, {Mette Norman} and T.H.V. Huynh and J.A. Ruiz and Isabell Haym and Bj{\o}rn-Yoshimoto, {Walden Emil} and Bjarke Abrahamsen and J. Hansen and M. Storgaard and A.L. Eriksen and Jensen, {Anders A.} and Lennart Bunch",

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T1 - New insights into the structure-activity-relationship of selective excitatory amino acid transporter subtype 1 (EAAT1) inhibitors UCPH-101 and UCPH-102

AU - Hansen, Stinne Wessel

AU - Erichsen, Mette Norman

AU - Huynh, T.H.V.

AU - Ruiz, J.A.

AU - Haym, Isabell

AU - Bjørn-Yoshimoto, Walden Emil

AU - Abrahamsen, Bjarke

AU - Hansen, J.

AU - Storgaard, M.

AU - Eriksen, A.L.

AU - Jensen, Anders A.

AU - Bunch, Lennart

PY - 2016/2/17

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N2 - In the present study, we made further investigations on the structure-activity requirements of the selective excitatory amino acid transporter 1 (EAAT1) inhibitor, 2-amino-4-(4-methoxyphenyl)-7-(naphthalen-1-yl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (UCPH-101), by exploring 15 different substituents (R1) at the 7-position in combination with eight different substituents (R2) at the 4-position. Among the 63 new analogues synthesized, we identified a number of compounds that unexpectedly displayed inhibitory activities at EAAT1 in light of understanding the structure-activity relationship (SAR) of this inhibitor class extracted from previous studies. Moreover, the nature of the R1 and R2 substituents were observed to contribute to the functional properties of the various analogues in additive and non-additive ways. Finally, separation of the four stereoisomers of analogue 14 g (2-amino-4-([1,1′-biphenyl]-4-yl)-3-cyano-7-isopropyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene) was carried out, and in agreement with a study of a related scaffold, the R configuration at C4 was found to be mandatory for inhibitory activity, while both the C7 diastereomers were found to be active as EAAT1 inhibitors. A study of the stereochemical stability of the four pure stereoisomers 14 g-A-D showed that epimerization takes places at C7 via a ring-opening, C-C bond rotation, ring-closing mechanism. Inhibition of glutamate uptake: 63 new analogues of the selective EAAT1 inhibitor UCPH-101 were synthesized and characterized pharmacologically. Analogues that unexpectedly displayed inhibitory activities at EAAT1 were identified. Furthermore, separation of the four stereoisomers of analogue 14 g revealed that, in agreement with a study of a related scaffold, the R configuration at C4 is mandatory for inhibitory activity, whereas both C7 diastereomers are active as EAAT1 inhibitors.

AB - In the present study, we made further investigations on the structure-activity requirements of the selective excitatory amino acid transporter 1 (EAAT1) inhibitor, 2-amino-4-(4-methoxyphenyl)-7-(naphthalen-1-yl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (UCPH-101), by exploring 15 different substituents (R1) at the 7-position in combination with eight different substituents (R2) at the 4-position. Among the 63 new analogues synthesized, we identified a number of compounds that unexpectedly displayed inhibitory activities at EAAT1 in light of understanding the structure-activity relationship (SAR) of this inhibitor class extracted from previous studies. Moreover, the nature of the R1 and R2 substituents were observed to contribute to the functional properties of the various analogues in additive and non-additive ways. Finally, separation of the four stereoisomers of analogue 14 g (2-amino-4-([1,1′-biphenyl]-4-yl)-3-cyano-7-isopropyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene) was carried out, and in agreement with a study of a related scaffold, the R configuration at C4 was found to be mandatory for inhibitory activity, while both the C7 diastereomers were found to be active as EAAT1 inhibitors. A study of the stereochemical stability of the four pure stereoisomers 14 g-A-D showed that epimerization takes places at C7 via a ring-opening, C-C bond rotation, ring-closing mechanism. Inhibition of glutamate uptake: 63 new analogues of the selective EAAT1 inhibitor UCPH-101 were synthesized and characterized pharmacologically. Analogues that unexpectedly displayed inhibitory activities at EAAT1 were identified. Furthermore, separation of the four stereoisomers of analogue 14 g revealed that, in agreement with a study of a related scaffold, the R configuration at C4 is mandatory for inhibitory activity, whereas both C7 diastereomers are active as EAAT1 inhibitors.

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DO - 10.1002/cmdc.201500525

M3 - Journal article

C2 - 26757239

SN - 1860-7179

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JO - Farmaco, Edizione Pratica

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ER -

New insights into the structure-activity-relationship of selective excitatory amino acid transporter subtype 1 (EAAT1) inhibitors UCPH-101 and UCPH-102

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