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

Stinne W Hansen, Mette N Erichsen, Tri H V Huynh, Josep A Ruiz, Isabell Haym, Walden E Bjørn-Yoshimoto, Bjarke Abrahamsen, Jeanette Hansen, Morten Storgaard, Anette L Eriksen, Anders A Jensen, Lennart Bunch

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

4 Citationer (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 (R(1) ) at the 7-position in combination with eight different substituents (R(2) ) 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 R(1) and R(2) 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.
OriginalsprogEngelsk
TidsskriftChemMedChem
Vol/bind11
Udgave nummer4
Sider (fra-til)382-402
Antal sider21
ISSN1860-7179
DOI
StatusUdgivet - 2016

Bibliografisk note

© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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