Hit-to-lead optimization of disubstituted oxadiazoles and tetrazoles as mGluR5 NAMs.
Here we report the discovery and early SAR of a series of mGluR5 negative allosteric modulators (NAMs). Starting from a moderately active HTS hit we synthesized 3,5-disubstituted-oxadiazoles and tetrazoles as mGluR5 NAMs. Based on the analysis of ligand efficiency and lipophilic efficiency metrics we identified a promising lead candidate as a starting point for further optimization.
Wágner
Gábor
G
Gedeon Richter Plc, Budapest, Hungary. g.wagner@richter.hu
Wéber
Csaba
C
Nyéki
Olga
O
Nógrádi
Katalin
K
Bielik
Attila
A
Molnár
László
L
Bobok
Amrita
A
Horváth
Attila
A
Kiss
Béla
B
Kolok
Sándor
S
Nagy
József
J
Kurkó
Dalma
D
Gál
Krisztina
K
Greiner
István
I
Szombathelyi
Zsolt
Z
Keseru
György M
GM
Domány
György
G
D000494:Allosteric Regulation / Q000187:drug effects*; D000818:Animals; D055808:Drug Discovery; D006801:Humans; D008024:Ligands; D010069:Oxadiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C578935:GRM5 protein, human; D008024:Ligands; D010069:Oxadiazoles; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D013777:Tetrazoles