title: 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).
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 R(1) 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.
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
authors.forename: Mette N
authors.initials: MN
authors.lastname: Erichsen
authors.forename: Tri H V
authors.initials: TH
authors.lastname: Huynh
authors.forename: Bjarke
authors.initials: B
authors.lastname: Abrahamsen
authors.forename: Jesper F
authors.initials: JF
authors.lastname: Bastlund
authors.forename: Christoffer
authors.initials: C
authors.lastname: Bundgaard
authors.forename: Olja
authors.initials: O
authors.lastname: Monrad
authors.forename: Anders
authors.initials: A
authors.lastname: Bekker-Jensen
authors.forename: Christina W
authors.initials: CW
authors.lastname: Nielsen
authors.forename: Karla
authors.initials: K
authors.lastname: Frydenvang
authors.forename: Anders A
authors.initials: AA
authors.lastname: Jensen
authors.forename: Lennart
authors.initials: L
authors.lastname: Bunch
mesh_terms: D000818:Animals; D001578:Benzopyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D001812:Blood-Brain Barrier / Q000378:metabolism; D018360:Crystallography, X-Ray; D027341:Excitatory Amino Acid Transporter 1 / Q000037:antagonists & inhibitors*; D007659:Ketones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D007769:Lactams / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D007783:Lactones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D008958:Models, Molecular; D009570:Nitriles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C553295:2-amino-4-(4-methoxyphenyl)-7-(naphthalen-1-yl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile; D001578:Benzopyrans; D027341:Excitatory Amino Acid Transporter 1; D007659:Ketones; D007769:Lactams; D007783:Lactones; D009570:Nitriles