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, 54 (21), 7639-47

Discovery, Synthesis, and Structure-Activity Relationship Development of a Series of N-4-(2,5-dioxopyrrolidin-1-yl)phenylpicolinamides (VU0400195, ML182): Characterization of a Novel Positive Allosteric Modulator of the Metabotropic Glutamate Receptor 4 (mGlu(4)) With Oral Efficacy in an Antiparkinsonian Animal Model

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Discovery, Synthesis, and Structure-Activity Relationship Development of a Series of N-4-(2,5-dioxopyrrolidin-1-yl)phenylpicolinamides (VU0400195, ML182): Characterization of a Novel Positive Allosteric Modulator of the Metabotropic Glutamate Receptor 4 (mGlu(4)) With Oral Efficacy in an Antiparkinsonian Animal Model

Carrie K Jones et al. J Med Chem.

Abstract

There is an increasing amount of literature data showing the positive effects on preclinical antiparkinsonian rodent models with selective positive allosteric modulators of metabotropic glutamate receptor 4 (mGlu(4)). However, most of the data generated utilize compounds that have not been optimized for druglike properties, and as a consequence, they exhibit poor pharmacokinetic properties and thus do not cross the blood-brain barrier. Herein, we report on a series of N-4-(2,5-dioxopyrrolidin-1-yl)phenylpicolinamides with improved PK properties with excellent potency and selectivity as well as improved brain exposure in rodents. Finally, ML182 was shown to be orally active in the haloperidol induced catalepsy model, a well-established antiparkinsonian model.

Figures

Figure 1
Figure 1
Structures of recently reported mGlu4 PAMs.
Figure 2
Figure 2
Structure of initial HTS hit.
Figure 10
Figure 10
Reversal of haloperidol-induced catalepsy in rats by compounds 15f after oral dosing. Catalepsy was measured in haloperidol treated (0.75 mg/kg) rats after oral administration of compound (0.1, 0.3, 1, 3, 10, 30 and 56.6 mg/kg) after 30 mins. An adenosine A2A antagonist from Neurocrine Biosciences was used as a positive control at 56.6 mg/kg, po.
Scheme 1
Scheme 1
Synthesis of 1,1,3,3-tetraoxidobenzo[d][1,3,2]dithiazol-2-yl)phenyl)carboxamides, 8a–l. a Reagents and conditions: (a) 1,2-benzenedisulfonyl dichloride, Et3N, CH2Cl2; (b) 4.0 M HCl/dioxane, 99% (2 steps); (c) RCOCl, CH2Cl2, DIEA, 49–87%; (d) RCO2H, EDCI, HOBt, dioxane/DMF, 27–74%. All library compounds were purified by mass-directed prep LC with a purity of >95%.
Scheme 2
Scheme 2
Synthesis of N-4-(2,5-dioxopyrrolidin-1-yl)-phenylpicolinamides.’a a Reagents and conditions: (a) Boc2O, DMAP, THF, reflux, 99%; (b) Pd/C, EtOAc, H2 (1 atm), rt; (c) Picolinoyl chloride HCl, CH2Cl2, pyridine, 84%; (d) 4.0 HCl/dioxane; (e) anhydride, toluene:AcOH (3:1), µW, 150 °C, 90 min. All library compounds were purified by mass-directed prep LC with a purity of >95%.

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