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2-Substituted (2SR)-2-Amino-2-((1SR,2SR)-2-carboxycycloprop-1-yl)glycines as Potent and Selective Antagonists of Group II Metabotropic Glutamate Receptors. 2. Effects of Aromatic Substitution, Pharmacological Characterization, and Bioavailability

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    2-Substituted (2SR)-2-Amino-2-((1SR,2SR)-2-carboxycycloprop-1-yl)glycines as Potent and Selective Antagonists of Group II Metabotropic Glutamate Receptors. 2. Effects of Aromatic Substitution, Pharmacological Characterization, and Bioavailability
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    Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285
    Lilly Development Centre S.A., Parc Scientifique de Louvain-la-Neuve, Rue Granbonpre, 11, 1348 Mont Saint-Guibert, Belgium
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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 1998, 41, 3, 358–378
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    https://doi.org/10.1021/jm970498o
    Published January 14, 1998
    Copyright © 1998 American Chemical Society
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    Abstract

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    In this paper we describe the synthesis of a series of α-substituted analogues of the potent and selective group II metabotropic glutamate receptor (mGluR) agonist (1S,1‘S,2‘S)-carboxycyclopropylglycine (2, L-CCG 1). Incorporation of a substituent on the amino acid carbon converted the agonist 2 into an antagonist. All of the compounds were prepared and tested as a series of four isomers, i.e., two racemic diastereomers. On the basis of the improvement in affinity realized for the α-phenylethyl analogue 3, in this paper we explored the effects of substitution on the aromatic ring as a strategy to increase the affinity of these compounds for group II mGluRs. Affinity for group II mGluRs was measured using [3H]glutamic acid (Glu) binding in rat forebrain membranes. Antagonist activity was confirmed for these compounds by measuring their ability to antagonize (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid-induced inhibition of forskolin stimulated cyclic-AMP in RGT cells transfected with human mGluR2 and mGluR3. Meta substitution on the aromatic ring of 3 with a variety of substituents, both electron donating (e.g., methyl, hydroxy, amino, methoxy, phenyl, phenoxy) and electron withdrawing (e.g., fluorine, chlorine, bromine, carboxy, trifluoromethyl) gave from 1.5- to 4.5-fold increases in affinity. Substitution with p-fluorine, as in 97 (IC50 = 0.022 ± 0.002), was the exception. Here, a greater increase in affinity was realized than for either the ortho- or meta-substituted analogues; 97 was the most potent compound resulting from monosubstitution of the aromatic. At best, only modest increases in affinity were realized for certain compounds bearing either two chlorines or two fluorines, and two methoxy groups gave no improvement in affinity (all examined in a variety of substitution patterns). Three amino acids, 4, 5, and 104, were resolved into their four constituent isomers, and affinity and functional activity for group II mGluRs was found to reside solely in the S,S,S-isomers of each, consistent with 1. With an IC50 = 2.9 ± 0.6 nM, the resolved xanthylmethyl compound 168 was the most potent compound from this SAR. Amino acid 168 demonstrated high plasma levels following intraperitoneal (ip) administration and readily penetrated into the brain. This compound, however, had only limited (∼5%) oral bioavailability. Systemic administration of 168 protected mice from limbic seizures produced by the mGluR agonist 3,5-dihydroxyphenylglycine, with an ED50 = 31 mg/kg (ip, 60 min preinjection). Thus, 168 represents a valuable tool to study the role of group II mGluRs in disease.

    Copyright © 1998 American Chemical Society

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     Address correspondence to:  Paul L. Ornstein, Lilly Research Laboratories, Lilly Corporate Center, DC 0510, Indianapolis, IN 46285. Phone:  317-276-3226. Fax:  317-276-7600. E-mail:  ornstein  paul@ lilly.com.

    Supporting Information Available

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    A list of all of the names of the amino acids prepared in this paper and 1H NMR spectra for compounds 165, 166, 177, 178, 189, and 190 (11 pages). Ordering information is given on any current masthead page.

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    Cite this: J. Med. Chem. 1998, 41, 3, 358–378
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    https://doi.org/10.1021/jm970498o
    Published January 14, 1998
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