We have synthesized a series of 1,3-dihydro-benzo<b>[1,4]diazepin-2-one derivatives, which are potent and selective negative allosteric modulators (NAM) of the metabotropic glutamate (mGlu) 2/3 receptor, and tested suitable compounds in cognition models in rodents and monkeys, e.g. an operant conditioning delayed match to position (DMTP) task and the Morris water maze. From the screening hit 1  the series evolved via compounds like 2  [1], 3  [2] and 4  [3] to the brain penetrant RO4491533 and RO4432717 [4]. They consistently showed in vivo activity after oral administration in both the DMTP task and in the Morris water maze. mGlu2/3 NAM dose-dependently attenuated the impairment of working memory induced by either the mGlu2/3 selective agonist LY354740 or scopolamine. Moreover, in combination studies with a cholinesterase inhibitor RO4491533 shows apparent synergistic effects on working memory impairment induced by scopolamine. For further profiling of mGlu2/3 NAM on cognition, RO4432717 was tested in aged Fischer 344 rats (22-24 months) and in a mouse model of Alzheimer's disease, PS2APP transgenic mice aged 12-13 months [5]. In the Morris water maze test RO4432717 significantly improved spatial acquisition in aged rats after 4 days of treatment and it rescued completely the spatial learning deficit observed in 12 month old PS2APP transgenic mice the after ten days of treatment. Finally, RO4432717 was shown to improve performance of a delayed matching to sample (DMTS) task in aged rhesus monkeys. References[1] Woltering, T. J.; Adam, G.; Alanine, A.; Wichmann, J.; Knoflach, F.; Mutel, V.; Gatti, S. Bioorg. Med. Chem. Lett. 2007 , 17(24), 6811-6815.[2] Woltering, T. J.; Adam, G.; Wichmann, J.; Goetschi, E.; Kew, J. N. C.; Knoflach, F.; Mutel, V.; Gatti, S. Bioorg. Med. Chem. Lett. 2008 , 18(3), 1091-1095.[3] Woltering, T. J.; Wichmann, J.; Goetschi, E.; Adam, G.; Kew, J. N. C.; Knoflach, F.; Ballard, T. M.; Huwyler, J.; Mutel, V.; Gatti, S. Bioorg. Med. Chem. Lett. 2008 , 18(8), 2725-2729.[4] Woltering, T. J.; Wichmann, J.; Goetschi, E.; Knoflach, F.; Ballard, T. M.; Huwyler, J.; Gatti, S. Bioorg. Med. Chem. Lett. 2010 , 20(23), 6969.[5] Richards, J.G.; Higgins, G.A.; Ouagazzal, A.M., Ozmen, L.; Kew, J.N.C.; Bohrmann, B., et al. J. Neurosci. 2003 , 23, 8989.

1,3-Dihydro-benzo[1,4]diazepin-2-one derivatives as selective mGlu2/3 NAM alleviate pharmacological or age-related cognitive impairment in rodents and monkeys

248th National Meeting (2014)

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