Synthesis, SARs, and Pharmacological Characterization of 2-Amino-3 or 6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic Acid Derivatives as Potent, Selective, and Orally Active Group II Metabotropic Glutamate Receptor Agonists

Abstract

(+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (4, LY354740), a highly selective and orally active group II metabotropic glutamate receptor (mGluR) agonist, has increased interest in the study of group II mGluRs. Our interest focused on a conformationally constrained form of compound 4, because it appeared that the rigid form resulted in not only selectivity for group II mGluR but was orally active. Therefore, we introduced a fluorine atom to compound 4, based on the molecular size (close resemblance to hydrogen atom) and electronegativity (effects on the electron distribution in the molecule) of this atom and carbon-fluorine bond energy. Compound (+)-7 (MGS0008), the best compound among 3-fluoro derivatives 7-10, retained the agonist activity of compound 4 for mGluR2 and mGluR3 ((+)-7: EC(50) = 29.4 +/- 3.3 nM and 45.4 +/- 8.4 nM for mGluR2 and mGluR3, respectively; 4: EC(50) = 18.3 +/- 1.6 nM and 62.8 +/- 12 nM for mGluR2 and mGluR3, respectively) and increased the oral activity of compound 4 ((+)-7: ED(50) = 5.1 mg/kg and 0.26 mg/kg for phencyclidine (PCP)-induced hyperactivity and PCP-induced head-weaving behavior, respectively; 4: ED(50) = >100 mg/kg and 3.0 mg/kg for PCP-induced hyperactivity and PCP-induced head-weaving behavior, respectively). In addition, a compound [(3)H]-(+)-7 binding study using mGluR2 or 3 expressed in CHO cells was successful ((+)-7: K(i) = 47.7 +/- 17 nM and 65.9 +/- 7.1 nM for mGluR2 and mGluR3, respectively; 4: K(i) = 23.4 +/- 7.1 nM and 53.5 +/- 13 nM for mGluR2 and mGluR3, respectively). On the basis of a successful result of compound 7, we focused on the introduction of a fluorine atom on the C6 position of compound 4. (1R,2S,5R, 6R)-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid ((-)-11) exhibited a high degree of agonist activity for group II mGluRs equal to that of compound 4 or 7 ((-)-11: K(i) = 16.6 +/- 5.6 and 80.9 +/- 31 nM for mGluR2 and mGluR3, respectively). Our interest shifted to modification on CH(2) at C4 position of compound 11, since replacement of the CH(2) group with either an oxygen atom or sulfur atom yielded compound 5 or 6, resulting in increased agonist activity. We selected a carbonyl group instead of CH(2) at the C4 position of compound 11. The carbonyl group might slightly change the relative conformation of three functional groups, the amino group and two carboxylic acids, which have important roles in mediating the interaction between group II mGluRs and their ligand, compared with the CH(2) group of 4, oxygen atom of 5, and sulfur atom of 6. (1R,2S,5S,6S)-2-Amino-6-fluoro-4-oxobicyclo[3.1. 0]hexane-2,6-dicarboxylic acid monohydrate ((+)-14, MGS0028) exhibited a remarkably high degree of agonist activity for mGluR2 (K(i) = 0.570 +/- 0.10 nM) and mGluR3 (K(i) = 2.07 +/- 0.40 nM) expressed in CHO cells but not mGluR4, 6, 7, 1a, or 5 expressed in CHO cells (K(i) = >100 000 nM). Furthermore, compound (+)-14 strongly inhibited phencyclidine (PCP)-induced head-weaving behavior (ED(50) = 0.090 microg/kg) and hyperactivity (ED(50) = 0.30 ...

Scalable Synthesis of (+)-2-Amino-3-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic Acid as a Potent and Selective Group II Metabotropic Glutamate Receptor Agonist

“…Finally, eliminating the phenylsulfinyl group of (Ϯ)-12 under neutral conditions in benzene yielded vinyl fluoride (Ϯ)-6a (34% yield). Fluorination of (Ϯ)-11 with NFSI proceeded at low temperatures in comparison to the method reported with KF · HF, 13) a nucleophilic fluorination reagent, giving (Ϯ)-6a as the sole product without elaborate separation by column chromatography.…”

“…20) We have already reported that (ϩ)-(1S,2S,3S,5R,6S)-2-amino-3-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (ϩ)-1 (MGS0008) was a potent and selective group II mGluR agonist. 13) Compound (Ϯ)-1 exhibited approximately 70-fold higher agonist activity than its diastereomer (Ϯ)-2 and (ϩ)-1 is approximately 90-fold as active as its enantiomer (Ϫ)-1 ( Fig. 1).…”

“…[3][4][5][6][7][8][9] Group I mGluRs (mGluR 1 and 5) activate phospholipase C, while both group II mGluRs (mGluR 2 and 3) and group III mGluRs (mGluR 4, 6, 7 and 8) inhibit adenyl cyclase. [9][10][11] Animal models and clinical trials suggest that agonists of group II mGluRs may be effective in treating a broad range of diseases and conditions, including schizophrenia, [13][14][15] anxiety, [16][17][18][19] and panic disorders. 20) We have already reported that (ϩ)-(1S,2S,3S,5R,6S)-2-amino-3-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (ϩ)-1 (MGS0008) was a potent and selective group II mGluR agonist.…”

“…13) Fluorination of epoxide (ϩ)-5a with potassium hydrogen difluoride (KF · HF) gave a key intermediate (Ϫ)-6a and an ester-exchange product (Ϫ)-7 in 18% and 28% yields, respectively. The requisite elaborate separation of (Ϫ)-6a and (Ϫ)-7 by silica gel column chromatography is unsuitable for large-scale synthesis.…”

Biological Evaluation of 2-Aryl-2-fluoropropionic Acids as Possible Platforms for New Medicinal Agents

“…First, there have been reported a few potent leads having a chiral fluorine-containing structure, such as fluorothalidomide, fluorodonepezil, etc. [6][7][8][9] These compounds were found to be pharmacologically more effective than the fluorine-free parent compounds. This suggests that the screening of biological activities of chiral fluorine-containing acids 1 could guide the development of new kinds of medicinal agents.…”