TY - JOUR

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 W

AU - Erichsen, Mette N

AU - Huynh, Tri H V

AU - Ruiz, Josep A

AU - Haym, Isabell

AU - Bjørn-Yoshimoto, Walden E

AU - Abrahamsen, Bjarke

AU - Hansen, Jeanette

AU - Storgaard, Morten

AU - Eriksen, Anette L

AU - Jensen, Anders A

AU - Bunch, Lennart

N1 - © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

PY - 2016

Y1 - 2016

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 (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.

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 (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.

KW - Benzopyrans/chemistry

KW - Excitatory Amino Acid Transporter 1/antagonists & inhibitors

KW - HEK293 Cells

KW - Humans

KW - Stereoisomerism

KW - Structure-Activity Relationship

U2 - 10.1002/cmdc.201500525

DO - 10.1002/cmdc.201500525

M3 - Journal article

C2 - 26757239

VL - 11

SP - 382

EP - 402

JO - Farmaco

JF - Farmaco

SN - 1860-7179

IS - 4

ER -