Synthesis, SAR, and Pharmacological Characterization of Brain Penetrant P2X7 Receptor Antagonists

ACS Medicinal Chemistry Letters

Volumn 6, Issue 6, 2015, Pages 671-676

  Savall, Brad M ^a   Wu, Duncan ^a   De Angelis, Meri ^a   Carruthers, Nicholas I ^a   Ao, Hong ^a   Wang, Qi ^a   Lord, Brian ^a   Bhattacharya, Anindya ^a   Letavic, Michael A ^a  

^a JANSSEN RESEARCH AND DEVELOPMENT   (Belgium)

Author keywords

depression; neuro inflammation; P2X7

Indexed keywords

1,2,3 TRIAZOLE DERIVATIVE; PIPERIDINE DERIVATIVE; PURINERGIC P2X RECEPTOR ANTAGONIST; PURINERGIC P2X7 RECEPTOR;

ANIMAL CELL; ANIMAL EXPERIMENT; ARTICLE; ARYLATION; AUTORADIOGRAPHY; DRUG BIOAVAILABILITY; DRUG CLEARANCE; DRUG HALF LIFE; DRUG SOLUBILITY; DRUG SYNTHESIS; ENZYME LINKED IMMUNOSORBENT ASSAY; EX VIVO STUDY; EXTRACTION RATIO; HUMAN; HUMAN CELL; HYDROGENATION; IN VITRO STUDY; IN VIVO STUDY; LIPOPHILICITY; METABOLIC STABILITY; NONHUMAN; PHYSICAL CHEMISTRY; PRIORITY JOURNAL; REDUCTION; STRUCTURE ACTIVITY RELATION; TRANSPORT ASSAY;

RATTUS; RODENTIA;

EID: 84931260794     PISSN: None     EISSN: 19485875     Source Type: Journal    
DOI: 10.1021/acsmedchemlett.5b00089     Document Type: Article

References (22)

1. Raison, C. L.; Capuron, L.; Miller, A. H. Cytokines sing the blues: inflammation and the pathogenesis of depression Trends Immunol. 2006, 27, 24-31
2. Dowlati, Y.; Herrmann, N.; Swardfager, W.; Liu, H.; Sham, L.; Reim, E. K.; Lanctot, K. L. A meta-analysis of cytokines in major depression Biol. Psychiatry 2010, 67, 446-57
3. Koo, J. W.; Duman, R. S. IL-1beta is an essential mediator of the antineurogenic and anhedonic effects of stress Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 751-6
4. Solle, M.; Labasi, J.; Perregaux, D. G.; Stam, E.; Petrushova, N.; Koller, B. H.; Griffiths, R. J.; Gabel, C. A. Altered cytokine production in mice lacking P2X(7) receptors J. Biol. Chem. 2001, 276, 125-32
5. Chrovian, C. C.; Rech, J. C.; Bhattacharya, A.; Letavic, M. A. P2X7 antagonists as potential therapeutic agents for the treatment of CNS disorders Prog. Med. Chem. 2014, 53, 65-100
6. Abberley, L.; Bebius, A.; Beswick, P. J.; Billinton, A.; Collis, K. L.; Dean, D. K.; Fonfria, E.; Gleave, R. J.; Medhurst, S. J.; Michel, A. D.; Moses, A. P.; Patel, S.; Roman, S. A.; Scoccitti, T.; Smith, B.; Steadman, J. G.; Walter, D. S. Identification of 2-oxo-N-(phenylmethyl)-4-imidazolidinecarboxamide antagonists of the P2X(7) receptor Bioorg. Med. Chem. Lett. 2010, 20, 6370-4
7. Abdi, M. H.; Beswick, P. J.; Billinton, A.; Chambers, L. J.; Charlton, A.; Collins, S. D.; Collis, K. L.; Dean, D. K.; Fonfria, E.; Gleave, R. J.; Lejeune, C. L.; Livermore, D. G.; Medhurst, S. J.; Michel, A. D.; Moses, A. P.; Page, L.; Patel, S.; Roman, S. A.; Senger, S.; Slingsby, B.; Steadman, J. G.; Stevens, A. J.; Walter, D. S. Discovery and structure-activity relationships of a series of pyroglutamic acid amide antagonists of the P2X7 receptor Bioorg. Med. Chem. Lett. 2010, 20, 5080-4
8. Beswick, P. J.; Billinton, A.; Chambers, L. J.; Dean, D. K.; Fonfria, E.; Gleave, R. J.; Medhurst, S. J.; Michel, A. D.; Moses, A. P.; Patel, S.; Roman, S. A.; Roomans, S.; Senger, S.; Stevens, A. J.; Walter, D. S. Structure-activity relationships and in vivo activity of (1H-pyrazol-4-yl)acetamide antagonists of the P2X7 receptor Bioorg. Med. Chem. Lett. 2010, 20, 4653-4656
9. Gleave, R. J.; Walter, D. S.; Beswick, P. J.; Fonfria, E.; Michel, A. D.; Roman, S. A.; Tang, S.-P. Synthesis and biological activity of a series of tetrasubstituted-imidazoles as P2X7 antagonists Bioorg. Med. Chem. Lett. 2010, 20, 4951-4954
10. Guile, S. D.; Alcaraz, L.; Birkinshaw, T. N.; Bowers, K. C.; Ebden, M. R.; Furber, M.; Stocks, M. J. Antagonists of the P2X(7) receptor. From lead identification to drug development J. Med. Chem. 2009, 52, 3123-41
11. Baxter, A.; Bent, J.; Bowers, K.; Braddock, M.; Brough, S.; Fagura, M.; Lawson, M.; McInally, T.; Mortimore, M.; Robertson, M.; Weaver, R.; Webborn, P. Hit-to-Lead studies: the discovery of potent adamantane amide P2X7 receptor antagonists Bioorg. Med. Chem. Lett. 2003, 13, 4047-50
12. Furber, M.; Alcaraz, L.; Bent, J. E.; Beyerbach, A.; Bowers, K.; Braddock, M.; Caffrey, M. V.; Cladingboel, D.; Collington, J.; Donald, D. K.; Fagura, M.; Ince, F.; Kinchin, E. C.; Laurent, C.; Lawson, M.; Luker, T. J.; Mortimore, M. M. P.; Pimm, A. D.; Riley, R. J.; Roberts, N.; Robertson, M.; Theaker, J.; Thorne, P. V.; Weaver, R.; Webborn, P.; Willis, P. Discovery of potent and selective adamantane-based small-molecule P2X7 receptor antagonists/interleukin-1β inhibitors J. Med. Chem. 2007, 50, 5882-5885
13. Duplantier, A. J.; Dombroski, M. A.; Subramanyam, C.; Beaulieu, A. M.; Chang, S. P.; Gabel, C. A.; Jordan, C.; Kalgutkar, A. S.; Kraus, K. G.; Labasi, J. M.; Mussari, C.; Perregaux, D. G.; Shepard, R.; Taylor, T. J.; Trevena, K. A.; Whitney-Pickett, C.; Yoon, K. Optimization of the physicochemical and pharmacokinetic attributes in a 6-azauracil series of P2X7 receptor antagonists leading to the discovery of the clinical candidate CE-224,535 Bioorg. Med. Chem. Lett. 2011, 21, 3708-11
14. Stock, T. C.; Bloom, B. J.; Wei, N.; Ishaq, S.; Park, W.; Wang, X.; Gupta, P.; Mebus, C. A. Efficacy and safety of CE-224,535, an antagonist of P2X7 receptor, in treatment of patients with rheumatoid arthritis inadequately controlled by methotrexate J. Rheumatol. 2012, 39, 720-7
15. Letavic, M. A.; Lord, B.; Bischoff, F.; Hawryluk, N. A.; Pieters, S.; Rech, J. C.; Sales, Z.; Velter, A. I.; Ao, H.; Bonaventure, P.; Contreras, V.; Jiang, X.; Morton, K. L.; Scott, B.; Wang, Q.; Wickenden, A. D.; Carruthers, N. I.; Bhattacharya, A. Synthesis and pharmacological characterization of two novel, brain penetrating P2X7 antagonists ACS Med. Chem. Lett. 2013, 4, 419-422
16. Bhattacharya, A.; Wang, Q.; Ao, H.; Shoblock, J. R.; Lord, B.; Aluisio, L.; Fraser, I.; Nepomuceno, D.; Neff, R. A.; Welty, N.; Lovenberg, T. W.; Bonaventure, P.; Wickenden, A. D.; Letavic, M. A. Pharmacological characterization of a novel centrally permeable P2X7 receptor antagonist: JNJ-47965567 Br. J. Pharmacol. 2013, 170, 624-40
17. Dean, D. K.; Munoz-Muriedas, J.; Sime, M.; Steadman, J. G. A.; Thewlis, R. E. A.; Trani, G.; Walter, D. S. Preparation of tetrahydro[1,2,4]triazolo[4,3-a]pyrazine derivatives for use as P2X7 modulators. WO 2008124153, April 2009.
18. Altman, R. A.; Koval, E. D.; Buchwald, S. L. Copper-catalyzed N-arylation of imidazoles and benzimidazoles J. Org. Chem. 2007, 72, 6190-6199
19. Antilla, J. C.; Baskin, J. M.; Barder, T. E.; Buchwald, S. L. Copper-diamine-catalyzed N-arylation of pyrroles, pyrazoles, indazoles, imidazoles, and triazoles J. Org. Chem. 2004, 69, 5578-5587
20. Khanna, I. K.; Weier, R. M. Regiospecific addition of Grignard reagents to the 4-position of activated imidazo[4,5-c]pyridine. A convenient method for the synthesis of 4-alkylarylimidazopyrazines Tetrahedron Lett. 1993, 34, 1885-1888
21. Chen, P.; Caldwell, C. G.; Mathvink, R. J.; Leiting, B.; Marsillo, F.; Patel, R. A.; Wu, J. K.; He, H.; Lyons, K. A.; Thornberry, N. A.; Weber, A. E. Imidazopiperidine amides as dipeptidyl peptidase IV inhibitors for the treatment of diabetes Bio. Org. Med. Chem. Lett. 2007, 17, 5853-5857
22. Ouellet, S. J.; Tuttle, J. B.; MacMillan, D. W. C. Enantioselective organocatalytic hydride reduction J. Am. Chem. Soc. 2005, 127, 32-33