A Selective Prostaglandin E2 Receptor Subtype 2 (EP2) Antagonist Increases the Macrophage-Mediated Clearance of Amyloid-Beta Plaques

Journal of Medicinal Chemistry

Volumn 58, Issue 13, 2015, Pages 5256-5273

  Fox, Brian M ^a   Beck, Hilary P ^a   Roveto, Philip M ^a   Kayser, Frank ^a   Cheng, Qingwen ^a   Dou, Hannah ^a   Williamson, Toni ^a   Treanor, James ^a   Liu, Hantao ^a   Jin, Lixia ^a   Xu, Guifen ^a   Ma, Ji ^a   Wang, Songli ^a   Olson, Steven H ^a  

^a AMGEN INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

3 [[7 (BENZO[B]THIOPHEN 3 YL) 9 METHOXY 2,3 DIHYDROBENZO[F][1,4]OXAZEPIN 4(5H) YL]METHYL]BENZONITRILE; 4 [[7 (BENZO[B]THIOPHEN 3 YL) 9 METHOXY 2,3 DIHYDROBENZO [F][1,4]OXAZEPIN 4(5H)YL]METHYL]BENZONITRILE; 5 [[7 (BENZO[B]THIOPHEN 3 YL) 9 METHOXY 2,3 DIHYDROBENZO [F][1,4]OXAZEPIN 4(5H) YL]METHYL]PYRIDIN 2 OL; 7 (2 CHLOROPHENYL) 9 METHOXY 4 (PYRIDIN 3 YLMETHYL) 2,3,4,5 TETRAHYDROBENZO[F][1,4]OXAZEPINE; 7 (3 CHLOROPHENYL) 9 METHOXY 4 (PYRIDIN 3 YLMETHYL) 2,3,4,5 TETRAHYDROBENZO[F][1,4]OXAZEPINE; 7 (4 CHLOROPHENYL) 9 METHOXY 4 (PYRIDIN 3 YLMETHYL) 2,3,4,5 TETRAHYDROBENZO[F][1,4]OXAZEPINE; 7 (BENZO[B]THIOPHEN 2 YL) 9 METHOXY 4 (PYRIDIN 3 YLMETHYL) 2,3,4,5 TETRAHYDROBENZO[F][1,4]OXAZEPINE; 7 (BENZO[B]THIOPHEN 3 YL) 4 (3 CHLOROBENZYL) 9 METHOXY 2,3,4,5 TETRAHYDROBENZO[F][1,4]OXAZEPINE; 7 (BENZO[B]THIOPHEN 3 YL) 4 (4 CHLOROBENZYL) 9 METHOXY 2,3,4,5 TETRAHYDROBENZO[F][1,4]OXAZEPINE; 7 (BENZO[B]THIOPHEN 3 YL) 4 BENZYL 9 METHOXY 2,3,4,5 TETRAHYDROBENZO[F][1,4]OXAZEPINE; 7 (BENZO[B]THIOPHEN 3 YL) 9 METHOXY 4 (4 METHOXYBENZYL)2,3,4,5 TETRAHYDROBENZO[F][1,4]OXAZEPINE; 7 (BENZO[B]THIOPHEN 3 YL) 9 METHOXY 4 (4 METHYLBENZYL) 2,3,4,5 TETRAHYDROBENZO[F][1,4]OXAZEPINE; 7 (BENZO[B]THIOPHEN 3 YL) 9 METHOXY 4 (PYRIDIN 2 YLMETHYL) 2,3,4,5 TETRAHYDROBENZO[F][1,4]OXAZEPINE; 7 (BENZO[B]THIOPHEN 3 YL) 9 METHOXY 4 (PYRIDIN 3 YL METHYL) 2,3,4,5 TETRAHYDROBENZO[F][1,4]OXAZEPINE; 7 (BENZO[B]THIOPHEN 3 YL) 9 METHOXY 4 (PYRIDIN 4 YLMETHYL) 2,3,4,5 TETRAHYDROBENZO[F][1,4]OXAZEPINE; 7 (BENZO[B]THIOPHEN 3 YL) 9 METHOXY 4 (PYRIMIDIN 5 YLMETHYL) 2,3,4,5 TETRAHYDROBENZO[F][1,4]OXAZEPINE; 7 (BENZO[B]THIOPHEN 3 YL) 9 METHOXY 4 [(2 METHOXYPYRIDIN 3 YL)METHYL] 2,3,4,5 TETRAHYDROBENZO[F][1,4]OXAZEPINE; 7 (BENZO[B]THIOPHEN 3 YL) 9 METHOXY 4 [(6 METHOXYPYRIDIN 3YL)METHYL] 2,3,4,5 TETRAHYDROBENZO[F][1,4]OXAZEPINE; 7 (BENZO[B]THIOPHEN 3 YL) 9 METHOXY 4 [4 (METHYLSULFONYL)BENZYL] 2,3,4,5 TETRAHYDROBENZO[F][1,4]OXAZEPINE; 9 METHOXY 4 (PYRIDIN 3 YLMETHYL) 7 (META TOLYL) 2,3,4,5TETRAHYDROBENZO[F][1,4]OXAZEPINE; 9 METHOXY 4 (PYRIDIN 3 YLMETHYL) 7 (ORTHO TOLYL) 2,3,4,5 TETRAHYDROBENZO[F][1,4]OXAZEPINE; 9 METHOXY 4 (PYRIDIN 3 YLMETHYL) 7 (PARA TOLYL) 2,3,4,5 TETRAHYDROBENZO[F][1,4]OXAZEPINE; 9 METHOXY 4 (PYRIDIN 3 YLMETHYL) 7 (THIOPHEN 3 YL) 2,3,4,5 TETRAHYDROBENZO[F][1,4]OXAZEPINE; 9 METHOXY 7 (NAPHTHALEN 1 YL) 4 (PYRIDIN 3 YLMETHYL) 2,3,4,5 TETRAHYDROBENZO[F][1,4]OXAZEPINE; 9 METHOXY 7 PHENYL 4 (PYRIDIN 3 YLMETHYL) 2,3,4,5 TETRAHYDROBENZO[F][1,4]OXAZEPINE; AMYLOID BETA PROTEIN; METHYL 4 [[7 (BENZO[B]THIOPHEN 3 YL) 9 METHOXY 2,3 DIHYDROBENZO[F][1,4]OXAZEPIN 4(5H) YL]METHYL]BENZOATE; PROSTAGLANDIN E RECEPTOR 2; PROSTAGLANDIN RECEPTOR BLOCKING AGENT; UNCLASSIFIED DRUG; UNINDEXED DRUG; 4-((9-CHLORO-7-(5-FLUORO-1H-INDOL-1-YL)-2,3-DIHYDROBENZO(F)(1,4)OXAZEPIN-4(5H)-YL)METHYL)PYRIDIN-2(1H)-ONE; OXAZEPINE DERIVATIVE; PYRIDONE DERIVATIVE;

AMYLOID PLAQUE; ANIMAL EXPERIMENT; ANIMAL TISSUE; ARTICLE; BRAIN HOMOGENATE; CAMP ASSAY; CENTRAL NERVOUS SYSTEM; DRUG INTERACTION; DRUG PENETRATION; ENZYME INHIBITION; HALF LIFE TIME; HUMAN; HUMAN TISSUE; IC50; LIVER MICROSOME; MACROPHAGE; METABOLIC STABILITY; MITSUNOBU REACTION; MOUSE; NONHUMAN; NUCLEOPHILICITY; PHAGOCYTOSIS; PROTEIN DEPLETION; RAT; SUZUKI REACTION; ANIMAL; ANTAGONISTS AND INHIBITORS; BIOASSAY; BRAIN; C57BL MOUSE; CHEMICAL STRUCTURE; CYTOLOGY; DRUG EFFECTS; METABOLISM; PROCEDURES; SPRAGUE DAWLEY RAT; STRUCTURE ACTIVITY RELATION; SYNTHESIS; TISSUE DISTRIBUTION;

ANIMALS; BIOLOGICAL ASSAY; BRAIN; MACROPHAGES; MICE; MICE, INBRED C57BL; MICROSOMES, LIVER; MOLECULAR STRUCTURE; OXAZEPINES; PHAGOCYTOSIS; PLAQUE, AMYLOID; PYRIDONES; RATS; RATS, SPRAGUE-DAWLEY; RECEPTORS, PROSTAGLANDIN E, EP2 SUBTYPE; STRUCTURE-ACTIVITY RELATIONSHIP; TISSUE DISTRIBUTION;

EID: 84937458800     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/acs.jmedchem.5b00567     Document Type: Article

References (50)

1. Braak, H.; Braak, E. Frequency of stages of Alzheimer-related lesions in different age categories Neurobiol. Aging 1997, 18, 351-357
2. Rogers, J.; Strohmeyer, R.; Kovelowski, C. J.; Li, R. Microglia and inflammatory mechanisms in the clearance of amyloid beta peptide Glia 2002, 40, 260-269
3. Shie, F.-S.; Breyer, R. M.; Montine, T. J. Microglia lacking E prostanoid receptor subtype 2 have enhanced Aβ phagocytosis yet lack Aβ-activated neurotoxicity Am. J. Pathol. 2005, 166, 1163-1172
4. Simard, A. R.; Soulet, D.; Gowing, G.; Julien, J.-P.; Rivest, S. Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer's disease Neuron 2006, 49, 489-502
5. Stalder, M.; Phinney, A.; Probst, A.; Sommer, B.; Staufenbiel, M.; Jucker, M. Association of microglia with amyloid plaques in brains of APP23 transgenic mice Am. J. Pathol. 1999, 154, 1673-1684
6. Frautschy, S. A.; Yang, F.; Irrizarry, M.; Hyman, B.; Saido, T. C.; Hsiao, K.; Cole, G. M. Microglial response to amyloid plaques in APPsw transgenic mice Am. J. Pathol. 1998, 152, 307-317
7. Perlmutter, L. S.; Scott, S. A.; Barron, E.; Chui, H. C. MHC class II-positive microglia in human brain: association with Alzheimer lesions J. Neurosci. Res. 1992, 33, 549-558
8. Dickson, D. W.; Farlo, J.; Davies, P.; Crystal, H.; Fuld, P.; Yen, S-H. C. A double-labeling immunohistochemical study of senile plaques Am. J. Pathol. 1988, 132, 86-101
9. Itagaki, S.; McGreer, P. L.; Akiyama, H.; Zhu, S.; Selkoe, D. Relationship of microglia and astrocytes to amyloid deposits of Alzheimer disease J. Neuroimmunol. 1989, 24, 173-182
10. Sheng, J. G.; Mrak, R. E.; Griffin, W. S. T. Neuritic plaque evolution in Alzheimer's disease is accompanied by transition of activated microglia from primed to enlarged to phagocytic forms Acta Neuropathol. 1997, 94, 1-5
11. Malm, T. N.; Koistinaho, M.; Pärepalo, M.; Vatanen, T.; Ooka, A.; Karlsson, S.; Koistinaho, J. Bone-marrow-derived cells contribute to the recruitment of microglial cells in response to beta-amyloid deposition in APP/PS1 double transgenic Alzheimer mice Neurobiol. Dis. 2005, 18, 134-142
12. Kalaria, R. N.; Cohen, D. L.; Premkumar, D. R. D. Cellular aspects of the inflammatory response in Alzheimer's disease Neurodegeneration 1996, 5, 497-503
13. Bacskai, B. J.; Kajdasz, S. T.; Christie, R. H.; Carter, C.; Games, D.; Seubert, P.; Schenk, D.; Hyman, B. T. Imaging of amyloid-β deposits in brains of living mice permits direct activation of clearance of plaques with immunotherapy Nature Med. 2001, 7, 369-372
14. Liu, Y.; Walter, S.; Stagi, M.; Cherny, D.; Letiembre, M.; Schulz-Schaeffer, W.; Heine, H.; Penke, B.; Neumann, H.; Fassbender, K. LPS receptor (CD14): a receptor for phagocytosis of Alzheimer's amyloid peptide Brain 2005, 128, 1778-1789
15. Nicoll, J. A. R.; Wilkinson, D.; Holmes, C.; Steart, P.; Markham, H.; Weller, R. O. Neuropathology of human Alzheimer disease after immunization with amyloid-β peptide: a case report Nature Med. 2003, 9, 448-452
16. Kim, S. U.; de Vellis, J. Microglia in health and disease J. Neurosci. Res. 2005, 81, 302-313
17. McDonald, D. R.; Brunden, K. R.; Landreth, G. E. Amyloid fibrils activate tyrosine kinase-dependent signaling and superoxide production in microglia J. Neurosci. 1997, 17, 2284-2294
18. Lue, L. F.; Walker, D. G.; Rogers, J. Modeling microglial activation in Alzheimer's disease with human postmortem microglial cultures Neurobiol. Aging 2001, 22, 945-956
19. Floden, A. M.; Li, S.; Combs, C. K. β-Amyloid-stimulated microglia induce neuron death via synergistic stimulation of tumor necrosis factor α and NMDA receptors J. Neurosci. 2005, 25, 2566-2575
20. Hickman, S. E.; Allison, E. K.; El Khoury, J. Microglial dysfunction and defective β-amyloid clearance pathways in aging Alzheimer's disease mice J. Neurosci. 2008, 28, 8354-8360
21. Krabbe, G.; Halle, A.; Matyash, V.; Rinnenthal, J. L.; Eom, G. D.; Bernhardt, U.; Miller, K. R.; Prokop, S.; Kettenmann, H.; Heppner, F. L. Functional impairment of microglia coincides with beta-amyloid deposition in mice with Alzheimer-like pathology PLoS One 2013, 8, e60921
22. Fiala, M.; Lin, J.; Ringman, J.; Kermani-Arab, V.; Tsao, G.; Patel, A.; Lossinsky, A. S.; Graves, M. C.; Gustavson, A.; Sayre, J.; Sofroni, E.; Suarez, T.; Chiappelli, F.; Bernard, G. Ineffective phagocytosis of amyloid-beta by macrophages of Alzheimer's disease patients J. Alzheimer's Dis. 2005, 7, 221-232
23. Mawuenyega, K. G.; Sigurdson, W.; Ovod, V.; Munsell, L.; Kasten, T.; Morris, J. C.; Yarasheki, K. E.; Bateman, R. J. Decreased clearance of CNS β-amyloid in Alzheimer's disease Science 2010, 330, 1774
24. Akiyama, H.; Barger, S.; Barnum, S.; Bradt, B.; Bauer, J.; Cole, G. M.; Cooper, N. R.; Eikelenboom, P.; Emmerling, M.; Fiebich, B. L.; Finch, C. E.; Frautschy, S.; Griffin, W. S. T.; Hampel, H.; Hull, M.; Landreth, G.; Lue, L.-F.; Mrak, R.; Mackenzie, I. R.; McGreer, P. L.; O'Banion, M. K.; Pachter, J.; Pasinetti, G.; Plata-Salaman, C.; Rogers, J.; Rydel, R.; Shen, Y.; Streit, W.; Strohmeyer, R.; Tooyoma, I.; Van Muiswinkel, F. L.; Veerhius, R.; Walker, D.; Webster, S.; Wegrzyniak, B.; Wenk, G.; Wyss-Coray, T. Inflammation and Alzheimer's disease Neurobiol. Aging 2000, 21, 383-421
25. 2 inhibits alveolar macrophage phagocytosis through an E-prostanoid 2 receptor-mediated increase in intracellular cyclic AMP J. Immunol. 2004, 173, 559-565
26. 2 levels in patients with probable AD Neurology 1999, 53, 1495-1498
27. Breyer, R. M.; Bagdassarian, C. K.; Myers, S. A.; Breyer, M. D. Prostanoid receptors: subtypes and signaling Annu. Rev. Pharmacol. Toxicol. 2001, 41, 661-690
28. Liang, X.; Wang, Q.; Hand, T.; Wu, L.; Breyer, R. M.; Montine, T. J.; Andreasson, K. Deletion of the prostaglandin E2 EP2 receptor reduces oxidative damage and amyloid burden in a model of Alzheimer's Disease J. Neurosci. 2005, 25, 10180-10187
29. 2 receptor subtype 2-null bone marrow Am. J. Pathol. 2010, 177, 346-354
30. 2 EP2 receptor in macrophages and brain microglia J. Neurosci. 2013, 33, 16016-16032
31. 2 receptor-dependent J. Neurochem. 2002, 83, 463-470
32. Shie, F.-S.; Montine, K. S.; Breyer, R. M.; Montine, T. J. Microglial EP2 is critical to neurotoxicity from activated cerebral innate immunity Glia 2005, 52, 70-77
33. Johansson, J. U.; Woodling, N. S.; Wang, Q.; Panchal, M.; Liang, X.; Trueba-Saiz, A.; Brown, H. D.; Mhatre, S. D.; Loui, T.; Andreasson, K. I. Prostaglandin signaling suppresses beneficial microglial function in Alzheimer's disease models J. Clin. Invest. 2015, 125, 350-364
34. Ganesh, T. Prostanoid receptor EP2 as a therapeutic target J. Med. Chem. 2014, 4454-4465
35. 2 receptor antagonist Br. J. Pharmacol. 2011, 164, 1847-1856
36. 2 receptor Br. J. Pharmacol. 2013, 168, 129-138
37. Jiang, J.; Ganesh, T.; Du, Y.; Quan, Y.; Serrano, G.; Qui, M.; Speigel, I.; Rojas, A.; Lelutiu, N.; Dingeldine, R. Small molecule antagonist reveals seizure-induced mediation of neuronal injury by prostaglandin E2 receptor subtype EP2 Proc. Natl. Acad. Sci. U. S. A. 2012, 109, 3149-3154
38. Jiang, J.; Quan, Y.; Ganesh, T.; Pouliot, W. A.; Dudek, F. E.; Dingledine, R. Inhibition of the prostaglandin receptor EP2 following status epilepticus reduces delayed mortality and brain inflammation Proc. Natl. Acad. Sci. U. S. A. 2013, 110, 3591-3596
39. Ganesh, T.; Jiang, J.; Shashidharamurthy, R.; Dingeldine, R. Discovery and characterization of carbamothioylacrylamides as EP2 selective antagonists ACS Med. Chem. Lett. 2013, 4, 616-621
40. Ganesh, T.; Jiang, J.; Dingeldine, R. Development of second generation EP2 antagonists with high selectivity Eur. J. Med. Chem. 2014, 82, 521-535
41. Ganesh, T.; Jiang, J.; Yang, M.-S.; Dingeldine, R. Lead optimization studies of cinnamic amide EP2 antagonists J. Med. Chem. 2014, 57, 4173-4184
42. Rendic, S.; Di Carlo, F. J. Human cytochrome P450 enzymes: a status report summarizing their reactions, substrates, inducers, and inhibitors Drug Metab. Rev. 1997, 29, 413-580
43. Riley, R. J.; Parker, A. J.; Trigg, S.; Manners, C. N. Development of a generalized, quantitative physicochemical model of CYP3A4 inhibition for use in early drug discovery Pharm. Res. 2001, 18, 652-655
44. Caggiano, A. O.; Kraig, R. P. Prostaglandin E receptor subtypes in cultured rat microglia and their role in reducing lipopolysaccharide-induced interleukin-1β production J. Neurochem. 1999, 72, 565-575
45. Hsiao, K.; Chapman, P.; Nilsen, S.; Eckman, C.; Harigaya, Y.; Younkin, S.; Yang, F.; Cole, G. Correlative memory deficits, Aβ elevation, and amyloid plaques in transgenic mice Science 1996, 274, 99-102
46. Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. Catalysts for Suzuki-Miyaura coupling processes: scope and studies of the effect of ligand structure J. Am. Chem. Soc. 2005, 127, 4685-4696
47. Node, M.; Kumar, K.; Nishide, K.; Ohsugi, S.-I.; Miyamoto, T. Odorless substitutes for foul-smelling thiols: syntheses and applications Tetrahedron Lett. 2001, 42, 9207-9210
48. Krow, G. R. Nitrogen insertion reactions of bridged bicyclic ketones. Regioselective lactam formation Tetrahedron 1981, 37, 1283-1307
49. Antilla, J. C.; Klapars, A.; Buchwald, S. L. The copper-catalyzed N-arylation of indoles J. Am. Chem. Soc. 2002, 124, 11684-11688
50. Liu, L.; Frohn, M.; Xi, N.; Dominguez, C.; Hungate, R.; Reider, P. J. A soluble base for the copper-catalyzed imidazole arylations with aryl halides J. Org. Chem. 2005, 70, 10135-10138