Structure-activity relationship study of first selective inhibitor of excitatory amino acid transporter subtype 1: 2-amino-4-(4-methoxyphenyl)-7-(naphthalen-1-yl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (UCPH-101)

Mette Norman Erichsen; Tri Hien Viet Huynh; Bjarke Abrahamsen; Jesper Frank Bastlund; Christoffer Bundgaard; Olja Monrad; Anders Bekker-Jensen; Christina Wøhlk Nielsen; Karla Andrea Frydenvang; Anders Asbjørn Jensen; Lennart Bunch

doi:10.1021/jm1009154

Structure-activity relationship study of first selective inhibitor of excitatory amino acid transporter subtype 1: 2-amino-4-(4-methoxyphenyl)-7-(naphthalen-1-yl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (UCPH-101)

Mette Norman Erichsen, Tri Hien Viet Huynh, Bjarke Abrahamsen, Jesper Frank Bastlund, Christoffer Bundgaard, Olja Monrad, Anders Bekker-Jensen, Christina Wøhlk Nielsen, Karla Andrea Frydenvang, Anders Asbjørn Jensen, Lennart Bunch

85 Citations (Scopus)

Abstract

The excitatory amino acid transporters (EAATs) are expressed throughout the central nervous system, where they are responsible for the reuptake of the excitatory neurotransmitter (S)-glutamate (Glu).(1)Recently, we have reported the discovery of the first subtype selective EAAT1 inhibitor 2-amino-4-(4-methoxyphenyl)-7-(naphthalen-1-yl)-5-oxo-5,6,7,8-tetrahydro-4H- chromene-3-carbonitrile (UCPH-101) (1b) and presented an introductory structure-activity relationship (SAR) study.(2)Here, we present a detailed SAR by the design, synthesis, and pharmacological evaluation of analogues 1g-1t. By comparison of potencies of 1b, 1h, and 1i versus 1j, it is evident that potency is largely influenced by the chemical nature of the R¹ substituent. The study also demonstrates that any chemical change of the functional groups or a change to the parental scaffold results in the complete loss of inhibitory activity of the compounds at EAAT1. Finally, a bioavailability study of UCPH-101 determined the half-life to be 30 min in serum (rats) but also that it was not able to penetrate the blood-brain barrier to any significant degree.

Original language	English
Journal	Journal of Medicinal Chemistry
Volume	53
Issue number	19
Pages (from-to)	7180–7191
ISSN	0022-2623
DOIs	https://doi.org/10.1021/jm1009154
Publication status	Published - 14 Oct 2010

Keywords

Former Faculty of Pharmaceutical Sciences

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Erichsen, M. N., Huynh, T. H. V., Abrahamsen, B., Bastlund, J. F., Bundgaard, C., Monrad, O., Bekker-Jensen, A., Nielsen, C. W., Frydenvang, K. A., Jensen, A. A., & Bunch, L. (2010). Structure-activity relationship study of first selective inhibitor of excitatory amino acid transporter subtype 1: 2-amino-4-(4-methoxyphenyl)-7-(naphthalen-1-yl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (UCPH-101). Journal of Medicinal Chemistry, 53(19), 7180–7191. https://doi.org/10.1021/jm1009154

Structure-activity relationship study of first selective inhibitor of excitatory amino acid transporter subtype 1: 2-amino-4-(4-methoxyphenyl)-7-(naphthalen-1-yl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (UCPH-101). / Erichsen, Mette Norman; Huynh, Tri Hien Viet; Abrahamsen, Bjarke et al.
In: Journal of Medicinal Chemistry, Vol. 53, No. 19, 14.10.2010, p. 7180–7191.

Research output: Contribution to journal › Journal article › Research › peer-review

Erichsen, MN, Huynh, THV, Abrahamsen, B, Bastlund, JF, Bundgaard, C, Monrad, O, Bekker-Jensen, A, Nielsen, CW, Frydenvang, KA , Jensen, AA & Bunch, L 2010, 'Structure-activity relationship study of first selective inhibitor of excitatory amino acid transporter subtype 1: 2-amino-4-(4-methoxyphenyl)-7-(naphthalen-1-yl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (UCPH-101)', Journal of Medicinal Chemistry, vol. 53, no. 19, pp. 7180–7191. https://doi.org/10.1021/jm1009154

Erichsen MN, Huynh THV, Abrahamsen B, Bastlund JF, Bundgaard C, Monrad O et al. Structure-activity relationship study of first selective inhibitor of excitatory amino acid transporter subtype 1: 2-amino-4-(4-methoxyphenyl)-7-(naphthalen-1-yl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (UCPH-101). Journal of Medicinal Chemistry. 2010 Oct 14;53(19):7180–7191. doi: 10.1021/jm1009154

Erichsen, Mette Norman ; Huynh, Tri Hien Viet ; Abrahamsen, Bjarke et al. / Structure-activity relationship study of first selective inhibitor of excitatory amino acid transporter subtype 1 : 2-amino-4-(4-methoxyphenyl)-7-(naphthalen-1-yl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (UCPH-101). In: Journal of Medicinal Chemistry. 2010 ; Vol. 53, No. 19. pp. 7180–7191.

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abstract = "The excitatory amino acid transporters (EAATs) are expressed throughout the central nervous system, where they are responsible for the reuptake of the excitatory neurotransmitter (S)-glutamate (Glu).(1)Recently, we have reported the discovery of the first subtype selective EAAT1 inhibitor 2-amino-4-(4-methoxyphenyl)-7-(naphthalen-1-yl)-5-oxo-5,6,7,8-tetrahydro-4H- chromene-3-carbonitrile (UCPH-101) (1b) and presented an introductory structure-activity relationship (SAR) study.(2)Here, we present a detailed SAR by the design, synthesis, and pharmacological evaluation of analogues 1g-1t. By comparison of potencies of 1b, 1h, and 1i versus 1j, it is evident that potency is largely influenced by the chemical nature of the R1 substituent. The study also demonstrates that any chemical change of the functional groups or a change to the parental scaffold results in the complete loss of inhibitory activity of the compounds at EAAT1. Finally, a bioavailability study of UCPH-101 determined the half-life to be 30 min in serum (rats) but also that it was not able to penetrate the blood-brain barrier to any significant degree.",

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AU - Huynh, Tri Hien Viet

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