Abstract：
:We have previously shown that the higher homologue of (S)-glutamic acid [(S)-Glu], (S)-alpha-aminoadipic acid [(S)-alpha-AA] is selectively recognized by the mGlu(2) and mGlu(6) subtypes of the family of metabotropic glutamic acid (mGlu) receptors. Furthermore, a number of analogues of (S)-alpha-AA, in which the terminal carboxyl group has been replaced by various bioisosteric groups, such as phosphonic acid or 3-isoxazolol groups, have been shown to interact selectively with different subtypes of mGlu receptors.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 alpha-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 alpha-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(2) (group II), and mGlu(4a) and mGlu(6) (group III) receptors, representing the three indicated groups of mGlu receptors.
journal_name
Eur J Med Chemjournal_title
European journal of medicinal chemistryauthors
Zimmermann D,Janin YL,Brehm L,Bräuner-Osborne H,Ebert B,Johansen TN,Madsen U,Krogsgaard-Larsen Pdoi
10.1016/s0223-5234(99)00122-1subject
Has Abstractpub_date
1999-11-01 00:00:00pages
967-976issue
11eissn
0223-5234issn
1768-3254pii
S0223-5234(99)00122-1journal_volume
34pub_type
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