3-pyrazolone analogues of the 3-isoxazolol metabotropic excitatory amino acid receptor agonist homo-AMPA. Synthesis and pharmacological testing

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D. Zimmermann, Y.L. Janin, L. Brehm, Hans Bräuner-Osborne, B. Ebert, T.N. Johansen, U. Madsen, P. Krogsgaard-Larsen

We have previously shown that the higher homologue of (S)-glutamic acid [(S)-Glu], (S)-a-aminoadipic acid [(S)-a-AA] is selectively recognized by the mGlu and mGlu subtypes of the family of metabotropic glutamic acid (mGlu) receptors. Furthermore, a number of analogues of (S)-a-AA, in which the terminal carboxyl group has been replaced by various bioisosteric groups, such as phosphonic acid or 3-isoxazolol groups, have been shown to interact selectively with different subtypes of mGlu receptors. In this paper we report the synthesis of the 3-pyrazolone bioisosteres of a-AA, compounds (RS)-2-amino-4-(1,2-dihydro-5-methyl-3-oxo-3H-pyrazol-4-yl)butyric acid (1) and (RS)-2-amino-4-(1,2-dihydro-1,5-dimethyl-3-oxo-3H-pyrazol-4-yl)butyric acid (2). At a number of steps in the reaction sequences used, the reactions took unexpected courses and provided products which could not be transformed into the target compounds, and attempts to synthesize the 2,5-dimethyl isomer of 2, compound 3, failed. An X-ray crystallographic analysis of the intermediate 1,2-dihydro-4-(2-hydroxyethyl)-2,5-dimethyl-3H-pyrazol-3-one (5b) confirmed the expected regioselectivity of the reaction between methylhydrazine and a-acetylbutyrolactone (4). Neither 1 nor 2 showed significant effects at the different types of ionotropic glutamic acid receptors or at mGlu(1a) (group I), mGlu (group II), and mGlu(4a) and mGlu (group III) receptors, representing the three indicated groups of mGlu receptors.
Original languageEnglish
JournalEuropean Journal of Medicinal Chemistry
Issue number11
Pages (from-to)967-976
Publication statusPublished - 1 Nov 1999

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