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

Journal of Medicinal Chemistry

Volumn 54, Issue 21, 2011, Pages 7639-7647

  Jones, Carrie K ^a,b   Engers, Darren W ^a,d   Thompson, Analisa D ^a   Field, Julie R ^a   Blobaum, Anna L ^a   Lindsley, Stacey R ^a   Zhou, Ya ^a   Gogliotti, Rocco D ^a   Jadhav, Satyawan ^a   Zamorano, Rocio ^a   Bogenpohl, Jim ^e   Smith, Yoland ^e   Morrison, Ryan ^a   Daniels, J Scott ^a   Weaver, C David ^a   Conn, P Jeffrey ^a,d   Lindsley, Craig W ^a,c,d   Niswender, Colleen M ^a   Hopkins, Corey R ^a,c,d  

^a VANDERBILT UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b DEPARTMENT OF VETERANS AFFAIRS   (United States)

^c Department of Chemistry ^*  (United States)

^d VANDERBILT UNIVERSITY MEDICAL CENTER   (United States)

^e EMORY UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIPARKINSON AGENT; HALOPERIDOL; METABOTROPIC RECEPTOR 4; ML 182; N [3 CHLORO 4 (1,3 DIOXO 2 AZASPIRO[4.5]DECAN 2 YL)PHENYL]PICOLINAMIDE; N [3 CHLORO 4 (2,5 DIOXO 3 PHENYLPYRROLIDIN 1 YL)PHENYL]PICOLINAMIDE; N [3 CHLORO 4 (BICYCLO[2.2.1]HEPT 5 ENE 1,3 DIOXO 1H ISOINDOL 1 YL)PHENYL]PICOLINAMIDE; PICOLINAMIDE; PYRROLIDINE DERIVATIVE; UNCLASSIFIED DRUG; VU 0400195;

ALLOSTERISM; ARTICLE; BLOOD BRAIN BARRIER; CATALEPSY; DISTRIBUTION VOLUME; DRUG BIOAVAILABILITY; DRUG CLEARANCE; DRUG EFFICACY; DRUG EXPOSURE; DRUG HALF LIFE; DRUG PENETRATION; DRUG POTENCY; DRUG PROTEIN BINDING; DRUG RECEPTOR BINDING; DRUG SELECTIVITY; DRUG SYNTHESIS; NONHUMAN; RODENT; STRUCTURE ACTIVITY RELATION;

ADMINISTRATION, ORAL; ALLOSTERIC REGULATION; ANIMALS; ANTIPARKINSON AGENTS; BIOLOGICAL AVAILABILITY; CATALEPSY; CHO CELLS; CRICETINAE; CRICETULUS; HALOPERIDOL; HUMANS; ISOINDOLES; MICROSOMES, LIVER; PICOLINIC ACIDS; RATS; RECEPTORS, METABOTROPIC GLUTAMATE; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 80455173693     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm200956q     Document Type: Article

References (28)

1. Dauer, W.; Przedborski, S. Parkinson's disease: mechanisms and models Neuron 2003, 39, 889-909
2. Schapira, A. H. V. Neurobiology and treatment of Parkinson's disease Trends Pharmacol. Sci. 2009, 30, 41-47
3. Hefti, F. F. Parkinson's Disease Drug Discovery Nerv. Syst. Dis. 2005, 183-204
4. Fahn, S. Description of Parkinson's disease as a clinical syndrome Ann. N.Y. Acad. Sci. 2003, 991, 1-14
5. Warner, T. T.; Schapira, A. H. V. Genetic and environmental factors in the cause of Parkinson's disease Ann. Neurol. 2003, 53, S16-S25
6. Jellinger, K. A. Recent developments in the pathology of Parkinson's disease J. Neural Transm. 2002, 62, 347-376
7. Parkinson, J. An Essay on the Shaking Palsy; London, Sherwood, Neely and Jones: London, 1817.
8. Fahn, S. The history of dopamine and levodopa in the treatment of Parkinson's disease Mov. Disord. 2008, 23, S497-S508
9. Baas, H.; Beiske, A. G.; Ghika, J.; Jackson, M.; Oertel, W. H.; Poewe, W.; Ransmayr, G. Catechol- O -methyltransferase inhibition with tolcapone reduces the "wearing off" phenomenom and levodopa requirements in fluctuating Parkinsonian patients Neurology 1998, 50, S46-S53
10. Stocchi, F. The levodopa wearing-off phenomenon in Parkinson's disease: pharmacokinetic considerations Exp. Opin. Pharmacother. 2006, 7, 1399-1407
11. Marek, K.; Jennings, D.; Seibyl, J. Do dopamine agonists or levodopa modify Parkinson's disease progression? Eur. J. Neurol. 2002, 9, 15-22
12. Conn, P. J.; Battaglia, G.; Marino, M. J.; Nicoletti, F. Metabotropic glutamate receptors in the basal ganglia motor circuit Nat. Rev. Neurosci. 2005, 6, 787-798
13. Conn, P. J.; Pin, J.-P. Pharmacology and functions of metabotropic glutamate receptors Annu. Rev. Pharmacol. Toxicol. 1997, 37, 205-237
14. Conn, P. J.; Christopoulos, A.; Lindsley, C. W. Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders Nat. Rev. Drug Discovery 2009, 8, 41-54
15. Cuomo, D.; Martella, G.; Barabino, E.; Platania, P.; Vita, D.; Madeo, G.; Selvam, C.; Goudet, C.; Oueslati, N.; Pin, J.-P.; Acher, F.; Pisani, A.; Beurrier, C.; Melon, C.; Kerkerian-LeGoff, L.; Gubellini, P. Metabotropic glutamate receptor subtype 4 selectively modulates both glutamate and GABA transmission in the striatum: implications for Parkinson's disease treatment J. Neurochem. 2009, 109, 1096-1105
16. Lindsley, C. W.; Niswender, C. M.; Engers, D. W.; Hopkins, C. R. Recent progress in the development of mGluR4 positive allosteric modulators for the treatment of Parkinson's disease Curr. Top. Med. Chem. 2009, 9, 949-963
17. Hopkins, C. R.; Lindsley, C. W.; Niswender, C. M. mGluR4 positive allosteric modulation as potential treatment of Parkinson's disease Future Med. Chem. 2009, 1, 501-513
18. Engers, D. W.; Niswender, C. M.; Weaver, C. D.; Jadhav, S.; Menon, U. N.; Zamorano, R.; Conn, P. J.; Lindsley, C. W.; Hopkins, C. R. Synthesis and evaluation of a series of heterobiarylamides that are centrally penetrant metabotropic glutamate receptor 4 (mGluR4) positive allosteric modulators (PAMs) J. Med. Chem. 2009, 52, 4115-4118
19. 4) with CNS exposure in rats J. Med. Chem. 2011, 54, 1106-1110
20. 4 receptor with efficacy in an animal model of motor dysfunction Bioorg. Med. Chem. Lett. 2010, 20, 4901-4905
21. Hopkins, C. R.; Niswender, C. M.; Lewis, L. M.; Weaver, C. D.; Lindsley, C. W. "Discovery of a potent, selective and in vivo active mGluR4 positive allosteric modulator" 2011, DOI: NBK50684. PMID: 21433377. http://www.ncbi.nlm.nih.gov/pubmed/21433377.
22. Niswender, C. M.; Lebois, E. P.; Luo, Q.; Kim, K.; Muchalski, H.; Yin, H.; Conn, P. J.; Lindsley, C. W. Positive allosteric modulators of the metabotropic glutamate receptor subtype 4 (mGluR4): Part I. Discovery of pyrazolo[3,4- d ]pyrimidines as novel mGluR4 positive allosteric modulators Bioorg. Med. Chem. Lett. 2008, 18, 5626-5630
23. Williams, R.; Niswender, C. M.; Luo, Q.; Le, U.; Conn, P. J.; Lindsley, C. W. Positive allosteric modulators of the metabotropic glutamate receptor subtype 4 (mGluR4). Part II: Challenges in hit-to-lead Bioorg. Med. Chem. Lett. 2009, 19, 962-966
24. 4 positive allosteric modulators (PAMs) identified by functional high-throughput screening (HTS) Bioorg. Med. Chem. Lett. 2010, 20, 5175-5178
25. i/o-linked G protein-coupled receptor coupling to potassium channels provides new insights into the pharmacology of the group III metabotropic glutamate receptors Mol. Pharmacol. 2008, 73, 1213-1224
26. Reynolds, I. J. Metabotropic Glutamate Receptors as Therapeutic Targets in Parkinson's Disease. Presented at the 6th International Meeting on Metabotropic Glutamate Receptors, Taormina, Sicily, Italy, September 14-19, 2008.
27. 2A receptor antagonists with in vivo efficacy J. Med. Chem. 2008, 51, 400-406
28. VU0400195 (ML182) has been declared a probe via the Molecular Libraries Probe Production Centers Network (MLPCN) and is available through the network. See http://mli.nih.gov/mli/.