In vitro ADME characterization of a very potent 3-acylamino-2-aminopropionic acid-derived GluN2C-NMDA receptor agonist and its ester prodrugs
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
Standard
In vitro ADME characterization of a very potent 3-acylamino-2-aminopropionic acid-derived GluN2C-NMDA receptor agonist and its ester prodrugs. / Bechthold, Elena; Grey, Lucie; Diamant, Emil; Schmidt, Judith; Steigerwald, Ruben; Zhao, Fabao; Hansen, Kasper B.; Bunch, Lennart; Clausen, Rasmus P.; Wünsch, Bernhard.
I: Biological Chemistry, Bind 404, Nr. 4, 2023, s. 255-265.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
TY - JOUR
T1 - In vitro ADME characterization of a very potent 3-acylamino-2-aminopropionic acid-derived GluN2C-NMDA receptor agonist and its ester prodrugs
AU - Bechthold, Elena
AU - Grey, Lucie
AU - Diamant, Emil
AU - Schmidt, Judith
AU - Steigerwald, Ruben
AU - Zhao, Fabao
AU - Hansen, Kasper B.
AU - Bunch, Lennart
AU - Clausen, Rasmus P.
AU - Wünsch, Bernhard
N1 - Funding Information: Research funding: This work was supported by the Research Training Group “Chemical biology of ion channels (Chembion)” funded by the Deutsche Forschungsgemeinschaft (DFG) [GRK 2515/1], which is gratefully acknowledged. The authors acknowledge financial support from the National Institutes of Health [NS097536] to K.B.H. Publisher Copyright: © 2022 Walter de Gruyter GmbH, Berlin/Boston.
PY - 2023
Y1 - 2023
N2 - The GluN2C subunit exists predominantly, but not exclusively in NMDA receptors within the cerebellum. Antagonists such as UBP1700 and positive allosteric modulators including PYD-106 and 3-acylamino-2-aminopropionic acid derivatives such as UA3-10 ((R)-2-amino-3-{[5-(2-bromophenyl)thiophen-2-yl]carboxamido}propionic acid) represent promising tool compounds to investigate the role of GluN2C-containing NMDA receptors in the signal transduction in the brain. However, due to its high polarity the bioavailability and CNS penetration of the amino acid UA3-10 are expected to be rather low. Herein, three ester prodrugs 12a-c of the NMDA receptor glycine site agonist UA3-10 were prepared and pharmacokinetically characterized. The esters 12a-c showed higher lipophilicity (higher logD7.4 values) than the acid UA3-10 but almost the same binding at human serum albumin. The acid UA3-10 was rather stable upon incubation with mouse liver microsomes and NADPH, but the esters 12a-c were fast hydrolyzed to afford the acid UA3-10. Incubation with pig liver esterase and mouse serum led to rapid hydrolysis of the esters 12a-c. The isopropyl ester 12c showed a promising logD7.4 value of 3.57 and the highest stability in the presence of pig liver esterase and mouse serum. These results demonstrate that ester prodrugs of UA3-10 can potentially afford improved bioavailability and CNS penetration.
AB - The GluN2C subunit exists predominantly, but not exclusively in NMDA receptors within the cerebellum. Antagonists such as UBP1700 and positive allosteric modulators including PYD-106 and 3-acylamino-2-aminopropionic acid derivatives such as UA3-10 ((R)-2-amino-3-{[5-(2-bromophenyl)thiophen-2-yl]carboxamido}propionic acid) represent promising tool compounds to investigate the role of GluN2C-containing NMDA receptors in the signal transduction in the brain. However, due to its high polarity the bioavailability and CNS penetration of the amino acid UA3-10 are expected to be rather low. Herein, three ester prodrugs 12a-c of the NMDA receptor glycine site agonist UA3-10 were prepared and pharmacokinetically characterized. The esters 12a-c showed higher lipophilicity (higher logD7.4 values) than the acid UA3-10 but almost the same binding at human serum albumin. The acid UA3-10 was rather stable upon incubation with mouse liver microsomes and NADPH, but the esters 12a-c were fast hydrolyzed to afford the acid UA3-10. Incubation with pig liver esterase and mouse serum led to rapid hydrolysis of the esters 12a-c. The isopropyl ester 12c showed a promising logD7.4 value of 3.57 and the highest stability in the presence of pig liver esterase and mouse serum. These results demonstrate that ester prodrugs of UA3-10 can potentially afford improved bioavailability and CNS penetration.
KW - 3-acylamino-2-aminopropionic acid derivatives
KW - GluN2C subtype-specific NMDA agonists
KW - hydrolytic stability
KW - in vitro ADME
KW - physicochemical parameters
KW - UA3-10
U2 - 10.1515/hsz-2022-0229
DO - 10.1515/hsz-2022-0229
M3 - Journal article
C2 - 36427206
AN - SCOPUS:85143065552
VL - 404
SP - 255
EP - 265
JO - Biological Chemistry
JF - Biological Chemistry
SN - 1431-6730
IS - 4
ER -
ID: 330836907