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<
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- 作者：Mette N. Erichsen ; Tri H. V. Huynh ; Bjarke Abrahamsen ; Jesper F. Bastlund ; Christoffer Bundgaard ; Olja Monrad ; Anders Bekker-Jensen ; Christina W. Nielsen ; Karla Frydenvang ; Anders A. Jensen ; Lennart Bu
- 刊名：Journal of Medicinal Chemistry
- 出版年：2010
- 出版时间：October 14, 2010
- 年：2010
- 卷：53
- 期：19
- 页码：7180-7191
- 全文大小：1090K
- 年卷期：v.53,no.19(October 14, 2010)
- ISSN：1520-4804
文摘
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.