Discovery and preclinical characterization of 1-methyl-3-(4-methylpyridin- 3-yl)-6-(pyridin-2-ylmethoxy)-1H-pyrazolo-[3,4-b]pyrazine (PF470): A highly potent, selective, and efficacious metabotropic glutamate receptor 5 (mGluR5) negative allosteric modulator

Journal of Medicinal Chemistry

Volumn 57, Issue 3, 2014, Pages 861-877

  Zhang, Lei ^a   Balan, Gayatri ^a   Barreiro, Gabriela ^a   Boscoe, Brian P ^a   Chenard, Lois K ^a   Cianfrogna, Julie ^a   Claffey, Michelle M ^a   Chen, Laigao ^a   Coffman, Karen J ^a   Drozda, Susan E ^a   Dunetz, Joshua R ^a   Fonseca, Kari R ^a   Galatsis, Paul ^a   Grimwood, Sarah ^a   Lazzaro, John T ^a   Mancuso, Jessica Y ^a   Miller, Emily L ^a   Reese, Matthew R ^a   Rogers, Bruce N ^a   Sakurada, Isao ^a   Skaddan, Marc ^a   Smith, Deborah L ^a   Stepan, Antonia F ^a   Trapa, Patrick ^a   Tuttle, Jamison B ^a   Verhoest, Patrick R ^a   Walker, Daniel P ^a   Wright, Ann S ^a   Zaleska, Margaret M ^a   Zasadny, Kenneth ^a   Shaffer, Christopher L ^a   more..

^a PFIZER INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE; ADMINISTRATION, ORAL; ALLOSTERIC REGULATION; ANIMALS; ANTIPARKINSON AGENTS; BIOLOGICAL AVAILABILITY; CELL MEMBRANE PERMEABILITY; DOGS; DYSKINESIA, DRUG-INDUCED; HEK293 CELLS; HUMANS; HYPERSENSITIVITY, DELAYED; LEVODOPA; MACACA FASCICULARIS; MADIN DARBY CANINE KIDNEY CELLS; MALE; MICROSOMES, LIVER; MODELS, MOLECULAR; PARKINSON DISEASE; PYRAZINES; PYRAZOLES; RADIOLIGAND ASSAY; RATS; RATS, SPRAGUE-DAWLEY; RECEPTOR, METABOTROPIC GLUTAMATE 5; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 84894071937     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm401622k     Document Type: Article

References (31)

1. Conn, P. J.; Pin, J.-P. Pharmacology and functions of metabotropic glutamate receptors Annu. Rev. Pharmacol. Toxicol. 1997, 37, 205-237
2. Bach, P.; Isaac, M.; Slassi, A. Metabotropic glutamate receptor 5 modulators and their potential therapeutic applications Expert Opin. Ther. Pat. 2007, 17, 371-384
3. Mela, F.; Marti, M.; Dekundy, A.; Danysz, W.; Morari, M.; Cenci, M. A. Antagonism of metabotropic glutamate receptor type 5 attenuates L-DOPA-induced dyskinesia and its molecular and neurochemical correlates in a rat model of Parkinson's disease J. Neurochem. 2007, 101, 483-497
4. Gasparini, F.; Lingenhöhl, K.; Stoehr, N.; Flor, P. J.; Heinrich, M.; Vranesic, I.; Biollaz, M.; Allgeier, H.; Heckendorn, R.; Urwyler, S.; Varney, M. A.; Johnson, E. C.; Hess, S. D.; Rao, S. P.; Sacaan, A. I.; Santori, E. M.; Velicelebi, G.; Kuhn, R. Methyl-6-(phenylethynyl)-pyridine (MPEP), a potent, selective and systematically active mGlu5 receptor antagonist Neuropharmacology 1999, 38, 493-503
5. Cosford, N. D. P.; Tehrani, L.; Roppe, J.; Schweiger, E.; Smith, N. D.; Anderson, J.; Bristow, L.; Brodkin, J.; Jiang, X.; McDonald, I.; Rao, S.; Washburn, M.; Varney, M. A. 3-[(2-Methyl-1,3-thiazol-4-yl)ethynyl]-pyridine: A potent and highly selective metabotropic glutamate subtype 5 receptor antagonist with anxiolytic activity J. Med. Chem. 2003, 46, 204-206
6. The structure of AFQ056 (Mavoglurant) was first disclosed in international nonproprietary names for pharmaceutical substances (INN). WHO Drug Information; World Health Organization: Geneva, Switzerland, 2010; Vol. 24, p 381.
7. The structure of ADX48621 (Dipraglurant) was first disclosed in international nonproprietary names for pharmaceutical substances (INN). WHO Drug Information; World Health Organization: Geneva, Switzerland, 2009; Vol. 23, p 328.
8. Morin, N.; Grégoire, L.; Gomez-Mancilla, B.; Gasparini, F.; Di Paolo, T. Effect of the metabotropic glutamate receptor type 5 antagonists MPEP and MTEP in parkinsonian monkeys Neuropharmacology 2010, 58, 981-986
9. Grégoire, L.; Morin, N.; Ouattara, B.; Gasparini, F.; Bilbe, G.; Johns, D.; Vranesic, I.; Sahasranaman, S.; Gomez-Mancilla, B.; Di Paolo, T. The acute antiparkinsonian and antidyskinetic effect of AFQ056, a novel metabotropic glutamate receptor type 5 antagonist, in L-DOPA-treated parkinsonian monkeys Parkinsonism Related Disord. 2011, 17, 270-276
10. Addex's ADX48621 effective in preclinical Parkinson's disease studies; Addex Pharmaceuticals Press Release: Geneva, Switzerland, 2010; http://www.addextherapeutics.com/investors/press-releases/.
11. Berg, D.; Godau, J.; Trenkwalder, C.; Eggert, K.; Csoti, I.; Storch, A.; Huber, H.; Morelli-Canelo, M.; Stamelou, M.; Ries, V.; Wolz, M.; Schnieder, C.; Di Paolo, T.; Gasparini, F.; Hariry, S.; Vandemeulebroecke, M.; Abi-Saab, W.; Cooke, K.; Johns, D.; Gomez-Mancilla, B. AFQ056 treatment of levodopa-induced dyskinesias: results of 2 randomized controlled trials Mov. Disord. 2011, 26, 1243-1250
12. Addex reports positive top line phase IIa data for dipraglurant in Parkinson's disease levodopa-induced dyskinesia (PD-LID). Addex Pharmaceuticals Press Release: Geneva, Switzerland, 2012; http://www.addextherapeutics.com/ investors/press-releases/.
13. Emmitte, K. A. mGlu5 negative allosteric modulators: A patent review (2010-2012) Expert Opin. Ther. Pat. 2013, 23, 393-408
14. For RG7090 structure, see: U.S. FDA Orphan Drug Designations and Approvals. http://www.accessdata.fda.gov/scripts/opdlisting/oopd/OOPD-Results-2. cfm?index-Number=333211.
15. Kalgutkar, A. S.; Gardner, I.; Obach, R. S.; Shaffer, C. L.; Callegari, E.; Henne, K. R.; Mutlib, A. E.; Dalvie, D. K.; Lee, J. S.; Nakai, Y.; O'Donnell, J. P.; Boer, J.; Harriman, S. P. A comprehensive listing of bioactivation pathways of organic functional groups Curr. Drug Metab. 2005, 6, 161-225
16. Hughes, Z. A.; Neal, S. J.; Smith, D. L.; Rizzo, S. J.; Pulicicchio, C. M.; Lotarski, S.; Lu, S.; Dwyer, J. M.; Brennan, J.; Olsen, M.; Bender, C. N.; Kouranova, E.; Andree, T. H.; Harrison, J. E.; Whiteside, G. T.; Springer, D.; O'Neil, S. V.; Leonard, S.; Schechter, L. E.; Dunlop, J.; Rosenzweig-Lipson, S.; Ring, R. H. Negative allosteric modulation of metabotropic glutamate receptor 5 results in broad spectrum activity relevant to treatment resistant depression Neuropharmacology 2013, 66, 202-214
17. Sperry, J. B.; Farr, R. M.; Levent, M.; Ghosh, M.; Hoagland, S. M.; Varsolona, R. J.; Sutherland, K. A robust process for an mGluR5 negative allosteric modulator: Difluoromethylation and Sonogashira coupling on large scale Org. Process Res. Dev. 2012, 16, 1854-1860
18. Wager, T. T.; Hou, X.; Verhoest, P. R.; Villalobos, A. Moving beyond rules: The development of a central nervous system multiparameter optimization (CNS MPO) approach to enable alignment of druglike properties ACS Chem. Neurosci. 2010, 1, 435-449
19. For a reference on ligand efficiency (LE), see: Hopkins, A. L.; Groom, C. R.; Alex, A. Ligand efficiency: A useful metric for lead selection Drug Discovery Today 2004, 9, 430-431
20. For a reference on lipophilicity efficiency (LipE), see: Freeman-Cook, K.; Hoffman, R. L.; Johnson, T. W. Lipophilicity efficiency: The most important efficiency metric in medicinal chemistry Future Med. Chem. 2013, 5, 113-115
21. Wager, T. T.; Chandrasekaran, R. Y.; Hou, X.; Troutman, M. D.; Verhoest, P. R.; Villalobos, A.; Will, Y. Defining desirable central nervous system drug space through the alignment of molecular properties, in vitro ADME and safety attributes ACS Chem. Neurosci. 2010, 1, 420-434
22. RRCK cells were generated in-house (Pfizer Inc., Groton, CT, USA) as a subclone of Mardin-Darby canine kidney wild-type (MDCK-WT) cells that displayed low expression of endogenous P-gp (approximately 1 to 2% of MDCK-WT cells based on mRNA level). For detailed information, see: Callegari, E.; Malhotra, B.; Bungay, P. J.; Webster, R.; Fenner, K. S.; Kempshall, S.; LaPerle, J. L.; Michel, M. C.; Kay, G. G. A comprehensive non-clinical evaluation of the CNS penetration potential of antimuscarinic agents for the treatment of overactive bladder Br. J. Clin. Pharmacol. 2011, 72, 235-246
23. Feng, B.; Mills, J. B.; Davidson, R. E.; Mireles, R. J.; Janiszewski, J. S.; Troutman, M. D.; de Morais, S. M. In vitro P-glycoprotein assays to predict the in vivo interactions of P-glycoprotein with drugs in the central nervous system Drug Metab. Dispos. 2008, 36, 268-275
24. Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings Adv. Drug Delivery Rev. 2001, 46, 3-26
25. Hughes, J. D.; Blagg, J.; Price, D. A.; Bailey, S.; DeCrescenzo, G. A.; Devraj, R. V.; Ellsworth, E.; Fobian, Y. M.; Gibbs, M. E.; Gilles, R. W.; Greene, N.; Huang, E.; Krieger-Burke, T.; Loesel, J.; Wager, T. T.; Whiteley, L.; Zhang, Y. Physicochemical drug properties associated with in vivo toxicology outcomes Bioorg. Med. Chem. Lett. 2008, 18, 4872-4875
26. 3H]3-methoxy-5-(pyridin-2-ylethynyl)pyridine Eur. J. Pharmacol. 2003, 473, 35-40
27. Rylander, D.; Iderberg, H.; Li, Q.; Dekundy, A.; Zhang, J.; Li, H.; Baishen, R.; Danysz, W.; Bezard, E.; Cenci, M. A. An mGluR5 antagonist under clinical development improves L-DOPA-induced dyskinesia in parkinsonian rats and monkeys Neurobiol. Dis. 2010, 39, 352-361
28. Palanisamy, G. S.; Marcek, J. M.; Cappon, G. D.; Whritenour, J.; Shaffer, C. L.; Brady, J. T.; Houle, C. Drug-induced cutaneous lesions in Cynomolgus macaques treated with metabotropic glutamate receptor 5 (mGluR5) negative allosteric modulators, 32nd Annual Symposium, Society of Toxicologic Pathology, Portland, OR, June 16-20, 2013; 88.
29. Yang, W.; Choong, I. Azaindazoles as HCV replication inhibitors and their preparation, pharmaceutical compositions and use in the treatment of flaviviridae virus infection. WO 2011/049987, April 28, 2011.
30. Cho, S.; Li, Q.; Ahn, S.; Bai, B.; Leahy, R. M. Iterative image reconstruction using inverse Fourier rebinning for fully 3-D PET IEEE Trans. Med. Imaging 2007, 26, 745-756
31. Cunningham, V. J.; Rabiner, E. A.; Slifstein, M.; Laruelle, M.; Gunn, R. N. Measuring drug occupancy in the absence of a reference region: The Lassen plot re-visited J. Cereb. Blood Flow Metab. 2010, 30, 46-50