3-(2-Ethoxy-4-{4-[3-hydroxy-2-methyl-4-(3-methylbutanoyl)phenoxy]butoxy}phenyl)propanoic acid: a brain penetrant allosteric potentiator at the metabotropic glutamate receptor 2 (mGluR2)
Graphical abstract
We have identified and synthesized a brain penetrant propanoic acid as an allosteric potentiator of the metabotropic glutamate receptor 2. Structure–activity relationship studies directed toward improving the potency, level of potentiation and brain penetration led to the discovery of 8 (EC50 = 1200 nM, 77% potentiation, 119% brain/plasma in rat, 20 mpk ip, brain level of 5700 nM).
Introduction
The neurotransmitter, glutamate, plays an important role in a wide variety of CNS functions, exerting its effect on both the ionotropic glutamate receptors, which are glutamate-gated ion channels, as well as the metabotropic glutamate receptors (mGlu), which are in the class of G-protein coupled receptors. Eight subtypes of the mGlu receptors fall into three main groups.1, 2 Group I consists of mGlu1 and −5, which have mainly been shown to be stimulatory. Groups II (mGlu2 and −3) and III (mGlu 4, −6, −7, −8), however, are often concentrated presynaptically and generally inhibit neurotransmission. Therefore, agents targeting the mGlu receptors may have utility in a variety of diseases3, 4, 5 including epilepsy, anxiety, and schizophrenia.6 The physiological importance of group II mGlu receptors has been shown by the efficacy of a rigid glutamate analogs such as (1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane 2,6-dicarboxylic acid7, 8 and (1R,2S,5S,6S)-2-amino-6-fluoro-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylic acid9 in both animal models as well as human clinical trials.10, 11 Both compounds are non-selective mGlu2/3 receptor agonists. Due to the high degree of sequence homology between group II mGlu receptors, selective agonists for mGlu2 over mGlu3 have not, as yet, been discovered. Therefore, another strategy for selectivity involves the discovery of allosteric modulators that do not bind at the glutamate binding site.12, 13, 14 This paper details the discovery and SAR of a class of selective mGlu2 receptor potentiators.
Screening15, 16, 17 of the Merck sample collection led to the discovery of tetrazole 1, which displayed moderate activity as an mGluR2 potentiator. Utilizing tetrazole 1 as the lead compound, three strategies were employed to improve the potency, level of potentiation and brain penetration. The first strategy focused on the modification of the acetophenone moiety, leading to the discovery of tetrazole 2.18 The second strategy investigated different linkers between the acetophenone and the phenyl tetrazole functional groups.18 The third strategy focused on the replacement of the tetrazole functionality with the goal of increasing brain penetration and hence improving the pK profile of the compounds. A variety of tetrazole replacements were examined, which led to the discovery of 4-thiopyridyl acetophenone (3) as a potent mGluR2 potentiator.19 During these efforts, 7-hydroxycoumarin (4) was also found to be a suitable tetrazole replacement. (EC50 1400 nM, 45% potentiation, with potentiation being defined as the response obtained using the test compound up to 10 μM plus an EC10 of glutamate normalized to the maximal response obtained with glutamate alone.) Compound 4 and the other analogs described below only showed activity at mGluR2 with no activity observed for mGluR3 as well as the other mGluRs. Herein we describe the detailed efforts on the replacement of the tetrazole with 7-hydroxycoumarin (4), chromanone, and propanoic acid functionalities.
Section snippets
Biology
Table 1 illustrates the SAR modifications of lead compound 4. Reduction of the 7-hydroxy-coumarin moiety to lactone 5 gave a favorable result of enhancing both the binding affinity (406 nM) and level of potentiation of 67% as compared to 4. Reduction and hydrolysis of the 7- hydroxycoumarin moiety to the carboxylic acid–phenol 6 also led to an improvement in potency when compared to lead 4 (1400–801 nM), but unfortunately no substantial increase in level of potentiation (45–66%) was observed. The
Chemistry
The synthesis for the 7-hydroxycoumarin compound 4 and its analogs described herein is outlined in Schemes Scheme 1, Scheme 2.21 The acetophenone derivatives 18 and 19, were alkylated with 1,4-dibromobutane, using potassium carbonate in acetone to afford the precursors 20 and 21, respectively. 7-Hydroxycoumarin was alkylated by these precursors to give compounds 4 and 10. Compound 4 was further hydrogenated in methanol to afford the methyl ester 7. Hydrolysis of 7 with lithium hydroxide
Conclusion
In summary, we have disclosed a new series of allosteric potentiators at the mGlu receptor 2 by replacing the tetrazole moiety of the lead compound 2 with 7-hydroxycoumarin type analogs. SAR strategies led to compounds with moderate potency, high levels of potentiation and good brain penetration. Although the lead tetrazole 2 showed good potency of 229 nM and a high level of potentiation of 89%, this compound was not brain penetrant. From this SAR, we have found a highly brain penetrant compound
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