Bioisosteric modifications of 2-arylureidobenzoic acids: selective noncompetitive antagonists for the homomeric kainate receptor subtype GluR5
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Bioisosteric modifications of 2-arylureidobenzoic acids : selective noncompetitive antagonists for the homomeric kainate receptor subtype GluR5. / Valgeirsson, Jon; Nielsen, Elsebet O; Peters, Dan; Mathiesen, Claus; Kristensen, Anders S; Madsen, Ulf.
In: Journal of Medicinal Chemistry, Vol. 47, No. 27, 30.12.2004, p. 6948-57.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Bioisosteric modifications of 2-arylureidobenzoic acids
T2 - selective noncompetitive antagonists for the homomeric kainate receptor subtype GluR5
AU - Valgeirsson, Jon
AU - Nielsen, Elsebet O
AU - Peters, Dan
AU - Mathiesen, Claus
AU - Kristensen, Anders S
AU - Madsen, Ulf
PY - 2004/12/30
Y1 - 2004/12/30
N2 - 2-Arylureidobenzoic acids (AUBAs) have recently been presented as the first series of selective noncompetitive GluR5 antagonists. In this paper we have modified the acidic moiety of the AUBAs by introducing different acidic and neutral groups, and similarly, we have replaced the urea linker of the AUBAs with other structurally related linkers. Replacing the acid with neutral substituents led to inactive compounds in all instances, showing that an acidic moiety is necessary for activity. Replacing the carboxylic moiety in 2a with a sulfonic acid (5c) or a tetrazole ring (5d) improved the potency at GluR5 receptors (compounds 5c and 5d showed IC(50) values of 1.5 and 2.0 muM, respectively, compared to compound 2a with IC(50) = 4.8 muM). Compound 5c did not show improved in vivo activity in the ATPA rigidity test compared to 2a, whereas compound 5d was 4 times more potent than 2a. All compounds wherein the urea linker had been replaced showed lower or no activity. The results described extend the knowledge of structure-activity relationships for the AUBAs, and compound 5d may prove to be a good candidate for studying GluR5 receptors in vitro and in vivo.
AB - 2-Arylureidobenzoic acids (AUBAs) have recently been presented as the first series of selective noncompetitive GluR5 antagonists. In this paper we have modified the acidic moiety of the AUBAs by introducing different acidic and neutral groups, and similarly, we have replaced the urea linker of the AUBAs with other structurally related linkers. Replacing the acid with neutral substituents led to inactive compounds in all instances, showing that an acidic moiety is necessary for activity. Replacing the carboxylic moiety in 2a with a sulfonic acid (5c) or a tetrazole ring (5d) improved the potency at GluR5 receptors (compounds 5c and 5d showed IC(50) values of 1.5 and 2.0 muM, respectively, compared to compound 2a with IC(50) = 4.8 muM). Compound 5c did not show improved in vivo activity in the ATPA rigidity test compared to 2a, whereas compound 5d was 4 times more potent than 2a. All compounds wherein the urea linker had been replaced showed lower or no activity. The results described extend the knowledge of structure-activity relationships for the AUBAs, and compound 5d may prove to be a good candidate for studying GluR5 receptors in vitro and in vivo.
KW - Animals
KW - Benzoates
KW - Dose-Response Relationship, Drug
KW - Female
KW - Humans
KW - Mice
KW - Rats
KW - Receptors, Kainic Acid
KW - Structure-Activity Relationship
U2 - 10.1021/jm030638w
DO - 10.1021/jm030638w
M3 - Journal article
C2 - 15615543
VL - 47
SP - 6948
EP - 6957
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 27
ER -
ID: 156344932