Discovery and Characterization of (R)-6-Neopentyl-2-(pyridin-2-ylmethoxy)-6,7-dihydropyrimido[2,1-c][1,4]oxazin-4(9H)-one (PF-06462894), an Alkyne-Lacking Metabotropic Glutamate Receptor 5 Negative Allosteric Modulator Profiled in both Rat and Nonhuman Primates

Journal of Medicinal Chemistry

Volumn 60, Issue 18, 2017, Pages 7764-7780

  Stepan, Antonia F ^a   Claffey, Michelle M ^a   Reese, Matthew R ^a   Balan, Gayatri ^a   Barreiro, Gabriela ^a   Barricklow, Jason ^a   Bohanon, Michael J ^a   Boscoe, Brian P ^a   Cappon, Gregg D ^a   Chenard, Lois K ^a   Cianfrogna, Julie ^a   Chen, Laigao ^a   Coffman, Karen J ^a   Drozda, Susan E ^a   Dunetz, Joshua R ^a   Ghosh, Somraj ^a   Hou, Xinjun ^a   Houle, Christopher ^a   Karki, Kapil ^a   Lazzaro, John T ^a   Mancuso, Jessica Y ^a   Marcek, John M ^a   Miller, Emily L ^a   Moen, Mark A ^a   O'Neil, Steven ^a   Sakurada, Isao ^a   Skaddan, Marc ^a   Parikh, Vinod ^a   Smith, Deborah L ^a   Trapa, Patrick ^a   Tuttle, Jamison B ^a   Verhoest, Patrick R ^a   Walker, Daniel P ^a   Won, Annie ^a   Wright, Ann S ^a   Whritenour, Jessica ^a   Zasadny, Kenneth ^a   Zaleska, Margaret M ^a   Zhang, Lei ^a   Shaffer, Christopher L ^a   more..

^a PFIZER INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

6 NEOPENTYL 2 (PYRIDIN 2 YLMETHOXY) 6,7 DIHYDROPYRIMIDO[2,1 C][1,4]OXAZIN 4(9H) ONE; AMINO ACID RECEPTOR AFFECTING AGENT; METABOTROPIC RECEPTOR 5; PF 06462894; UNCLASSIFIED DRUG; FUSED HETEROCYCLIC RINGS; PF-06462894; PYRIDINE DERIVATIVE;

ALKYLATION; ANIMAL EXPERIMENT; ANIMAL TISSUE; ARTICLE; DISEASE SEVERITY; DRUG BIOAVAILABILITY; DRUG CLEARANCE; DRUG HALF LIFE; DRUG HYPERSENSITIVITY; HEK293 CELL LINE; HEK293-FT CELL LINE; HIGH THROUGHPUT SCREENING; HISTOPATHOLOGY; HUMAN; HUMAN CELL; LIVER MICROSOME; NONHUMAN; RAT; SKIN TOXICITY; ALLOSTERISM; ANIMAL; ANTAGONISTS AND INHIBITORS; CHEMISTRY; DRUG EFFECTS; FEMALE; MALE; METABOLISM; MOLECULAR DOCKING; SPRAGUE DAWLEY RAT; STRUCTURE ACTIVITY RELATION;

ALLOSTERIC REGULATION; ANIMALS; FEMALE; HEK293 CELLS; HETEROCYCLIC COMPOUNDS, 3-RING; HUMANS; MALE; MOLECULAR DOCKING SIMULATION; PYRIDINES; RATS; RATS, SPRAGUE-DAWLEY; RECEPTOR, METABOTROPIC GLUTAMATE 5; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 85030324429     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/acs.jmedchem.7b00604     Document Type: Article

References (44)

1. Crawford, J. H.; Wainwright, A.; Heavens, R.; Pollock, J.; Martin, D. J.; Scott, R. H.; Seabrook, G. R. Mobilization of intracellular Ca2+ by mGluR5 metabotropic glutamate receptor activation in neonatal rat cultured dorsal root ganglia neurones Neuropharmacology 2000, 39, 621-630 10.1016/S0028-3908(99)00167-7
2. Recasens, M.; Guiramand, J.; Aimar, R.; Abdulkarim, A.; Barbanel, G. Metabotropic glutamate receptors as drug targets Curr. Drug Targets 2007, 8, 651-681 10.2174/138945007780618544
3. Swanson, C. J.; Bures, M.; Johnson, M. P.; Linden, A.-M.; Monn, J. A.; Schoepp, D. D. Metabotropic glutamate receptors as novel targets for anxiety and stress disorders Nat. Rev. Drug Discovery 2005, 4, 131-144 10.1038/nrd1630
4. Pin, J. P.; Duvoisin, R. Review: neurotransmitter receptors I. The metabotropic glutamate receptors: structure and functions Neuropharmacology 1995, 34, 1-26 10.1016/0028-3908(94)00129-G
5. Conn, P. J.; Pin, J.-P. Pharmacology and functions of metabotropic glutamate receptors Annu. Rev. Pharmacol. Toxicol. 1997, 37, 205-237 10.1146/annurev.pharmtox.37.1.205
6. Spooren, W. P. J. M.; Vassout, A.; Neijt, H. C.; Kuhn, R.; Gasparini, F.; Roux, S.; Porsolt, R. D.; Gentsch, C. Anxiolytic-like effects of the prototypical metabotropic glutamate receptor 5 antagonist 2-methyl-6-(phenylethynyl)pyridine in rodents J. Pharmacol. Exp. Ther. 2000, 295, 1267-1275
7. Walker, K.; Reeve, A.; Bowes, M.; Winter, J.; Wotherspoon, G.; Davis, A.; Schmid, P.; Gasparini, F.; Kuhn, R.; Urban, L. mGlu5 receptors and nociceptive function. II. mGlu5 receptors functionally expressed on peripheral sensory neurones mediate inflammatory hyperalgesia Neuropharmacology 2001, 40, 10-19 10.1016/S0028-3908(00)00114-3
8. Tatarczynska, E.; Klodzinska, A.; Chojnacka-Wojcik, E.; Palucha, A.; Gasparini, F.; Kuhn, R.; Pilc, A. Potential anxiolytic- and antidepressant-like effects of MPEP, a potent, selective and systemically active mGlu5 receptor antagonist br J. Pharmacol. 2001, 132, 1423-1430 10.1038/sj.bjp.0703923
9. Chapman, A. G.; Nanan, K.; Williams, M.; Meldrum, B. S. Anticonvulsant activity of two metabotropic glutamate Group I antagonists selective for the mGlu5 receptor: 2-methyl-6-(phenylethynyl)-pyridine (MPEP), and (E)-6-methyl-2-styryl-pyridine (SIB 1893) Neuropharmacology 2000, 39, 1567-1574 10.1016/S0028-3908(99)00242-7
10. Bruno, V.; Ksiazek, I.; Battaglia, G.; Lukic, S.; Leonhardt, T.; Sauer, D.; Gasparini, F.; Kuhn, R.; Nicoletti, F.; Flor, P. J. Selective blockade of metabotropic glutamate receptor subtype 5 is neuroprotective Neuropharmacology 2000, 39, 2223-2230 10.1016/S0028-3908(00)00079-4
11. Ossowska, K.; Konieczny, J.; Wolfarth, S.; Wieronska, J.; Pilc, A. Blockade of the metabotropic glutamate receptor subtype 5 (mGluR5) produces antiparkinsonian-like effects in rats Neuropharmacology 2001, 41, 413-420 10.1016/S0028-3908(01)00083-1
12. Chiamulera, C.; Epping-Jordan, M. P.; Zocchi, A.; Marcon, C.; Cottiny, C.; Tacconi, S.; Corsi, M.; Orzi, F.; Conquet, F. Reinforcing and locomotor stimulant effects of cocaine are absent in mGluR5 null mutant mice Nat. Neurosci. 2001, 4, 873-874 10.1038/nn0901-873
13. O'Neil, M. J.; Fell, M. J.; Svensson, K. A.; Witkin, J. M.; Mitchell, S. N. Recent developments in metabotropic glutamate receptors as novel drug targets Drugs Future 2010, 35, 307-324 10.1358/dof.2010.035.04.1487693
14. Nicoletti, F.; Bockaert, J.; Collingridge, G. L.; Conn, P. J.; Ferraguti, F.; Schoepp, D. D.; Wroblewski, J. T.; Pin, J. P. Metabotropic glutamate receptors: From the workbench to the bedside Neuropharmacology 2011, 60, 1017-1041 10.1016/j.neuropharm.2010.10.022
15. Rocher, J.-P.; Bonnet, B.; Bolea, C.; Lutjens, R.; Le Poul, E.; Poli, S.; Epping-Jordan, M.; Bessis, A.-S.; Ludwig, B.; Mutel, V. mGluR5 negative allosteric modulators overview: a medicinal chemistry approach towards a series of novel therapeutic agents Curr. Top. Med. Chem. (Sharjah, United Arab Emirates) 2011, 11, 680-695 10.2174/1568026611109060680
16. Fuxe, K.; Borroto-Escuela, D. O. Basimglurant for treatment of major depressive disorder: a novel negative allosteric modulator of metabotropic glutamate receptor 5 Expert Opin. Invest. Drugs 2015, 24, 1247-1260 10.1517/13543784.2015.1074175
17. Quiroz, J. A.; Tamburri, P.; Deptula, D.; Banken, L.; Beyer, U.; Rabbia, M.; Parkar, N.; Fontoura, P.; Santarelli, L. Efficacy and Safety of Basimglurant as Adjunctive Therapy for Major Depression: A Randomized Clinical Trial JAMA Psychiatry 2016, 73, 675-684 10.1001/jamapsychiatry.2016.0838
18. Micheli, F. Methylphenyl ethynyl pyridine (MPEP)(Novartis) Curr. Opin. Invest. Drugs 2000, 1, 355-359
19. 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 10.2174/1389200054021799
20. Stepan, A. F.; Walker, D. P.; Bauman, J.; Price, D. A.; Baillie, T. A.; Kalgutkar, A. S.; Aleo, M. D. Structural alert/reactive metabolite concept as applied in medicinal chemistry to mitigate the risk of idiosyncratic drug toxicity: A perspective based on the critical examination of trends in the top 200 drugs marketed in the United States Chem. Res. Toxicol. 2011, 24, 1345-1410 10.1021/tx200168d
21. Emmitte, K. A. mGlu5 negative allosteric modulators: a patent review (2013-2016) Expert Opin. Ther. Pat. 2017, 27, 691-706 10.1080/13543776.2017.1280466
22. Raboisson, P.; Breitholtz-Emanuelsson, A.; Dahlloef, H.; Edwards, L.; Heaton, W. L.; Isaac, M.; Jarvie, K.; Kers, A.; Minidis, A. B. E.; Nordmark, A.; Sheehan, S. M.; Slassi, A.; Stroem, P.; Terelius, Y.; Wensbo, D.; Wilson, J. M.; Xin, T.; McLeod, D. A. Discovery and characterization of AZD9272 and AZD6538-Two novel mGluR5 negative allosteric modulators selected for clinical development Bioorg. Med. Chem. Lett. 2012, 22, 6974-6979 10.1016/j.bmcl.2012.08.100
23. Mueller, R.; Dawson, E. S.; Meiler, J.; Rodriguez, A. L.; Chauder, B. A.; Bates, B. S.; Felts, A. S.; Lamb, J. P.; Menon, U. N.; Jadhav, S. B.; Kane, A. S.; Jones, C. K.; Gregory, K. J.; Niswender, C. M.; Conn, P. J.; Olsen, C. M.; Winder, D. G.; Emmitte, K. A.; Lindsley, C. W. Discovery of 2-(2-benzoxazoyl amino)-4-aryl-5-cyanopyrimidine as negative allosteric modulators (NAMs) of metabotropic glutamate receptor 5 (mGlu5): From an artificial neural network virtual screen to an in vivo tool compound ChemMedChem 2012, 7, 406-414 10.1002/cmdc.201100510
24. The full PF number of PF470 is PF-06297470.
25. Zhang, L.; Balan, G.; Barreiro, G.; Boscoe, B. P.; Chenard, L. K.; Cianfrogna, J.; Claffey, M. M.; Chen, L.; Coffman, K. J.; Drozda, S. E.; Dunetz, J. R.; Fonseca, K. R.; Galatsis, P.; Grimwood, S.; Lazzaro, J. T.; Mancuso, J. Y.; Miller, E. L.; Reese, M. R.; Rogers, B. N.; Sakurada, I.; Skaddan, M.; Smith, D. L.; Stepan, A. F.; Trapa, P.; Tuttle, J. B.; Verhoest, P. R.; Walker, D. P.; Wright, A. S.; Zaleska, M. M.; Zasadny, K.; Shaffer, C. L. 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 J. Med. Chem. 2014, 57, 861-877 10.1021/jm401622k
26. Palanisamy, G. S.; Marcek, J. M.; Cappon, G. D.; Whritenour, J.; Shaffer, C. L.; Brady, J. T.; Houle, C. Drug-induced skin lesions in cynomolgus macaques treated with metabotropic glutamate receptor 5 (mGluR5) negative allosteric modulators Toxicol. Pathol. 2015, 43, 995-1003 10.1177/0192623315588114
27. Kremer, K. A. M.; Krishnan, L.; Venkatesan, A. M.; Jennings, M.; Zeldis, J.; Abe, T.; Mansour, T.; Strong, H. Processes for Preparing Bicyclic Oxazine Carboxaldehyde and β-Lactamase Inhibitors. WO2009/006243A2, Jan 8, 2009.
28. Abass, M.; Mayas, A. S. Substituted pyridopyrimidinones, 1: Convenient PTC alkylation and halogenation of 2-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one Heteroat. Chem. 2007, 18, 19-27 10.1002/hc.20245
29. 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 10.1111/j.1365-2125.2011.03961.x
30. 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 10.1124/dmd.107.017434
31. Leeson, P. D.; Springthorpe, B. The influence of drug-like concepts on decision-making in medicinal chemistry Nat. Rev. Drug Discovery 2007, 6, 881-890 10.1038/nrd2445
32. Ryckmans, T.; Edwards, M. P.; Horne, V. A.; Correia, A. M.; Owen, D. R.; Thompson, L. R.; Tran, I.; Tutt, M. F.; Young, T. Rapid assessment of a novel series of selective CB2 agonists using parallel synthesis protocols: A Lipophilic Efficiency (LipE) analysis Bioorg. Med. Chem. Lett. 2009, 19, 4406-4409 10.1016/j.bmcl.2009.05.062
33. Stepan, A. F.; Kauffman, G. W.; Keefer, C. E.; Verhoest, P. R.; Edwards, M. Evaluating the differences in cycloalkyl ether metabolism using the design parameter ″Lipophilic Metabolism Efficiency″ (LipMetE) and a matched molecular pairs analysis J. Med. Chem. 2013, 56, 6985-6990 10.1021/jm4008642
34. Gehlhaar, D. K.; Verkhivker, G. M.; Rejto, P. A.; Sherman, C. J.; Fogel, D. B.; Fogel, L. J.; Freer, S. T. Molecular recognition of the inhibitor AG-1343 by HIV-1 protease: Conformationally flexible docking by evolutionary programming Chem. Biol. 1995, 2, 317-324 10.1016/1074-5521(95)90050-0
35. Lovering, F.; Bikker, J.; Humblet, C. Escape from flatland: Increasing saturation as an approach to improving clinical success J. Med. Chem. 2009, 52, 6752-6756 10.1021/jm901241e
36. Sherman, W.; Beard, H. S.; Farid, R. Use of an induced fit receptor structure in virtual screening Chem. Biol. Drug Des. 2006, 67, 83-84 10.1111/j.1747-0285.2005.00327.x
37. Dore, A. S.; Okrasa, K.; Patel, J. C.; Serrano-Vega, M.; Bennett, K.; Cooke, R. M.; Errey, J. C.; Jazayeri, A.; Khan, S.; Tehan, B.; Weir, M.; Wiggin, G. R.; Marshall, F. H. Structure of class C GPCR metabotropic glutamate receptor 5 transmembrane domain Nature (London, U. K.) 2014, 511, 557-562 10.1038/nature13396
38. Rylander, D.; Iderberg, H.; Li, Q.; Dekundy, A.; Zhang, J.; Li, H.; Baishen, R.; Danysz, W.; Bezard, E.; Cenci, M. A. A mGluR5 antagonist under clinical development improves L-DOPA-induced dyskinesia in parkinsonian rats and monkeys Neurobiol. Dis. 2010, 39, 352-361 10.1016/j.nbd.2010.05.001
39. Whritenour, J.; Cole, S.; Zhu, X.; Li, D.; Kawabata, T. T. Development and partial validation of a mouse model for predicting drug hypersensitivity reactions J. Immunotoxicol. 2014, 11, 141-147 10.3109/1547691X.2013.812164
40. Soglia, J. R.; Harriman, S. P.; Zhao, S.; Barberia, J.; Cole, M. J.; Boyd, J. G.; Contillo, L. G. The development of a higher throughput reactive intermediate screening assay incorporating micro-bore liquid chromatography-micro-electrospray ionization-tandem mass spectrometry and glutathione ethyl ester as an in vitro conjugating agent J. Pharm. Biomed. Anal. 2004, 36, 105-116 10.1016/j.jpba.2004.04.019
41. Shaffer, C. L. The discovery and preclinical characterization of the novel mGluR5 negative allosteric modulator PF470: Implications for mechanism-based toxicity Curr. Neuropharmacol. 2014, 12 (Suppl 1) 55-56
42. Shah, F.; Stepan, A. F.; O'Mahony, A.; Velichko, S.; Folias, A. E.; Houle, C.; Shaffer, C. L.; Marcek, J.; Whritenour, J.; Stanton, R.; Berg, E. L. Mechanisms of skin toxicity associated with metabotropic glutamate receptor 5 negative allosteric modulators Cell Chem. Biol. 2017, 24, 858-869 10.1016/j.chembiol.2017.06.003
43. Hosea, N. A.; Collard, W. T.; Cole, S.; Maurer, T. S.; Fang, R. X.; Jones, H.; Kakar, S. M.; Nakai, Y.; Smith, B. J.; Webster, R.; Beaumont, K. Prediction of human pharmacokinetics from preclinical information: comparative accuracy of quantitative prediction approaches J. Clin. Pharmacol. 2009, 49, 513-533 10.1177/0091270009333209
44. Ertl, P.; Rohde, B.; Selzer, P. Fast calculation of molecular polar surface area as a sum of fragment-based contributions and its application to the prediction of drug transport properties J. Med. Chem. 2000, 43, 3714-3717 10.1021/jm000942e