Discovery and kinetic profiling of 7-aryl-1,2,4-triazolo[4,3-a]pyridines: positive allosteric modulators of the metabotropic glutamate receptor 2.

Discovery and kinetic profiling of 7-aryl-1,2,4-triazolo[4,3-a]pyridines: positive allosteric modulators of the metabotropic glutamate receptor 2.

J Med Chem. 2017 Jul 13;:

Authors: Doornbos MLJ, Cid JM, Haubrich J, Nunes A, van de Sande JW, Vermond SC, Mulder-Krieger T, Trabanco AA, Ahnaou A, Drinkenburg WH, Lavreysen H, Heitman LH, IJzerman AP, Tresadern G

Abstract
We report the synthesis and biological evaluation of a series of 7-aryl-1,2,4-triazolo[4,3-a]pyridines with mGlu2 positive allosteric modulator (PAM) activity and affinity. Besides traditional in vitro parameters of potency and affinity, kinetic parameters kon, koff and residence time (RT) were determined. The PAMs showed various kinetic profiles; kon values ranged over two orders of magnitude, whereas RT values were within a 10-fold range. Association rate constant kon was linearly correlated to affinity. Evaluation of a short, medium and long RT compound in a label-free assay indicated a correlation between RT and functional effect. The effects of long RT compound 9 on sleep-wake states indicated long RT was translated into sustained inhibition of rapid eye movement (REM) in vivo. These results show that affinity-only driven selection would have resulted in mGlu2 PAMs with high values for kon, but not necessarily optimized RT, which is key to predict optimal efficacy in vivo.

PMID: 28704052 [PubMed - as supplied by publisher]

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