Synthesis and Structure–Activity Relationship Studies of Novel 2-Diarylethyl Substituted (2-Carboxycycloprop-1-yl)glycines as High-Affinity Group II Metabotropic Glutamate Receptor Ligands

doi:10.1016/S0968-0896(02)00387-5

Bioorganic & Medicinal Chemistry

Volume 11, Issue 2, January 2003, Pages 197-205

https://doi.org/10.1016/S0968-0896(02)00387-5 Get rights and content

Abstract

The major excitatory neurotransmitter in the central nervous system, (S)-glutamic acid (1), activates both ionotropic and metabotropic excitatory amino acid receptors. Its importance in connection to neurological and psychiatric disorders has directed great attention to the development of compounds that modulate the effects of this endogenous ligand. Whereas l-carboxycyclopropylglycine (l-CCG-1, 2) is a potent agonist at, primarily, group II metabotropic glutamate receptors, alkylation of 2 at the α-carbon notoriously result in group II mGluR antagonists, of which the most potent compound described so far, LY341495 (12), displays IC₅₀ values of 23 and 10 nM at the group II receptor subtypes mGlu2 and mGlu3, respectively. In this study we synthesized a series of structural analogues of 12 in which the xanthyl moiety is replaced by two substituted-phenyl groups. The pharmacological characterization shows that these novel compounds have very high affinity for group II mGluRs when tested as their racemates. The most potent analogues demonstrate K_i values in the range of 5–12 nM, being thus comparable to LY341495 (12).

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Introduction

(S)-Glutamic acid (1) is the major excitatory neurotransmitter in the central nervous system (CNS), and activates both ionotropic and metabotropic excitatory amino acid (EAA) receptors. The three subclasses of ionotropic EAA receptors are N-methyl-d-aspartic (NMDA),1, 2 2-amino-3-(5-methyl-3-hydroxyisoxazol-4-yl)propanoic acid (AMPA),3, 4, 5, 6 and kainic acid (KA) receptors.3, 4, 5, 7, 8 In contrast to these ligand gated ion channel receptors, the metabotropic glutamate receptors (mGluRs) are G-protein coupled receptors, linked to multiple signal transduction pathways, including phosphatidylinositide and cyclic-AMP production.9, 10, 11

Based on sequence homology and pharmacological properties, three subclasses of mGluRs have so far been identified; group I (comprising the receptor subtypes mGlu1 and mGlu5), group II (mGlu2 and mGlu3), and group III (mGlu4, mGlu6, mGlu7, and mGlu8). The mGluRs have not yet been as well characterized pharmacologically as the ionotropic glutamate receptors, but it is generally agreed that all classes of EAA receptors play important roles in the CNS, and that ligands affecting ionotropic12, 13 as well as metabotropic12, 13, 14, 15, 16, 17 receptors would serve as useful therapeutic targets in relation to various neurologic disorders.

A large number of mGluR ligands have been developed, of which l-carboxycyclopropylglycine (l-CCG-1, 2),¹⁸ 2-amino-4-phosphonobutanoic acid (l-AP4, 3),¹⁹ and (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R)-ACPD, 4)²⁰ were among the first potent agonists identified. Compound 3 is a relatively selective group III agonist whereas 4 shows activity at both group I and group II mGluRs. Also, the potent group II mGluR agonist 2 shows some activity at group I mGluRs. These structures have helped lead the way for further development aimed at understanding the pharmacology of the mGluRs. An example of a potent and selective group II agonist is LY354740 (5).21, 22, 23, 24, 25 The recently described heterocyclic derivatives of 5, LY379268 (6) and LY389795 (7),22, 26 have displayed EC₅₀ values between 3 and 8 nM, and are among the most potent group II mGluR agonists known to date. Also, modification of 3 led to α-methyl-AP4 (MAP-4, 8), a selective but relatively nonpotent group III mGluR antagonist.²⁷

We previously made a detailed structure activity relationship (SAR) study showing that substitution of 2 in the α-position of the amino acid moiety with an alkyl or especially arylalkyl substituent has a marked effect on both potency and selectivity.28, 29 Thus, systematic substitution with unbranched and branched alkyl chains led to compound 9 with an IC₅₀ in glutamate binding of 1.4 μM.²⁸

Further elaboration of 9 to the cyclohexylmethyl analogue 10 and the phenylethyl derivative 11 led to a further increase in glutamate binding affinity (IC₅₀ 0.23 and 0.32 μM, respectively). The most potent compound synthesized in this series was the 9-xanthylmethyl derivative,²⁸ of which the S,S,S-stereoisomer, LY341495 (12),28, 30 displayed IC₅₀ values of 23 and 10 nM at mGlu2 and mGlu3 receptors, respectively. LY341495 has now been developed into a useful radioligand.31, 32, 33 Modification of 12 into its 3′-ethyl analogue CECXG (13) improves overall group II selectivity but also gives a 5-fold loss of potency.³⁴

Compared to compound 11, the introduction of an additional phenyl group to give compound 14 gives not only improved potency (IC₅₀ 0.24 μM) but also a 16-fold increase in selectivity for mGlu3 relative to mGlu2.²⁸ This finding has prompted us to study whether substituents on the phenyl groups of 14 would further improve selectivity as well as potency. This paper reports the synthesis and pharmacological characterization of a number of analogues of 14 containing a variety of different phenyl ring substituents.

Section snippets

Chemistry

A number of the novel amino acid derivatives 22 presented in this paper were synthesized by our previously published pathway with only minor changes in the procedure (Scheme 1).28, 29 All of the compounds that we prepared contain multiple racemic diastereomers. Through the synthetic methods utilized, we typically obtained a nearly 1:1 or 1:1:1 ratio of diastereomers, and no attempt was made to separate these diastereomers; nor did we do anything to separate the different enantionmeric pairs.

Pharmacology

We found that all of the α-alkylated analogues of l-CCG-1 (2) described in our earlier studies were potent antagonists at group II mGlu receptors.28, 29 Therefore, we only tested compounds synthesized in this study for their binding affinity to the two cloned human mGluR group II subtypes, mGlu2 and mGlu3. These assays were performed in competition with radiolabelled LY341495 (12).32, 33, 39 Furthermore, to show whether group I activity is also present, all compounds were tested on mGlu1 and

Acknowledgements

The authors thank the Physical Chemistry Department of Lilly Research Laboratories for ¹³C NMR spectra as well as MS and elemental analyses. Also a special thanks to Jack Campbell, Lilly Research Laboratories, for the liberal use of his high-pressure hydrogenation equipment.

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Synthesis and Structure–Activity Relationship Studies of Novel 2-Diarylethyl Substituted (2-Carboxycycloprop-1-yl)glycines as High-Affinity Group II Metabotropic Glutamate Receptor Ligands

Abstract

Introduction

Section snippets

Chemistry

Pharmacology

Acknowledgements

Neuropharmacology

Pharmacol. Ther.

Progr. Brain Res.

Trends Pharmacol. Sci.

Progr. Neurobiol.

Trends Pharmacol. Sci.

Annu. Rep. Med. Chem.

Neuropharmacology

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Neuropharmacology

Neurosci. Lett.

Neuropharmacology

Bioorg. Med. Chem. Lett.

Neuropharmacology

Bioorg. Med. Chem. Lett.

Tetrahedron Lett.

Physiol. Rev.