Design, synthesis, and pharmacological evaluation of glutamate carboxypeptidase II (GCPII) inhibitors based on thioalkylbenzoic acid scaffolds.
A series of thiol-based glutamate carboxypeptidase II (GCPII) inhibitors have been synthesized with either a 3-(mercaptomethyl)benzoic acid or 2-(2-mercaptoethyl)benzoic acid scaffold. Potent inhibitors were identified from each of the two scaffolds with IC(50) values in the single-digit nanomolar range, including 2-(3-carboxybenzyloxy)-5-(mercaptomethyl)benzoic acid 27c and 3-(2-mercaptoethyl)biphenyl-2,3'-dicarboxylic acid 35c. Compound 35c was found to be metabolically stable and selective over a number of targets related to glutamate-mediated neurotransmission. Furthermore, compound 35c was found to be orally available in rats and exhibited efficacy in an animal model of neuropathic pain following oral administration.
Eisai Inc., Baltimore, Maryland 21224, United States.
Doris
D
Stoermer
Dilrukshi
D
Vitharana
Niyada
N
Hin
Greg
G
Delahanty
Bridget
B
Duvall
Dana V
DV
Ferraris
Brian S
BS
Grella
Randall
R
Hoover
Camilo
C
Rojas
Megan K
MK
Shanholtz
Kyle P
KP
Smith
Marigo
M
Stathis
Ying
Y
Wu
Krystyna M
KM
Wozniak
Barbara S
BS
Slusher
Takashi
T
Tsukamoto
D000818:Animals; D001565:Benzoates / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors*; D006801:Humans; D020128:Inhibitory Concentration 50; D009437:Neuralgia / Q000188:drug therapy; D051381:Rats
D001565:Benzoates; D004791:Enzyme Inhibitors; D043425:Glutamate Carboxypeptidase II