Discovery and optimization of 1-(4-(Pyridin-2-yl)benzyl)imidazolidine-2,4- dione derivatives as a novel class of selective cannabinoid CB2 receptor agonists

Journal of Medicinal Chemistry

Volumn 54, Issue 20, 2011, Pages 7350-7362

  Van Der Stelt, Mario ^a,b   Cals, Jos ^a   Broeders Josten, Silvia ^a   Cottney, Jean ^a   Van Der Doelen, Antoon A ^a   Hermkens, Marcel ^a   De Kimpe, Vera ^a   King, Angela ^a   Klomp, Jan ^a   Oosterom, Julia ^a   Pols De Rooij, Ilse ^a   De Roos, Jeroen ^a   Van Tilborg, Martin ^a   Boyce, Susan ^a   Baker, James ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

^b Netherlands Translational Research Center BV   (Netherlands)

Author keywords

[No Author keywords available]

Indexed keywords

1 [4 (5 FLUORO 6 MORPHOLIN 4 YLMETHYLPYRIDIN 2 YL)BENZYL] 3 ISOBUTYLIMIDAZOLIDINE 2,4 DIONE; 1 [4 (PYRIDIN 2 YL)BENZYL]IMIDAZOLIDINE 2,4 DIONE DERIVATIVE; 1 [4 [5 FLUORO 6 (PIPERIDIN 1 YLMETHYL)PYRIDIN 2 YL]BENZYL] 3 ISOBUTYLIMIDAZOLIDINE 2,4 DIONE; 1 [4 [5 FLUORO 6 (PIPERIDIN 1 YLMETHYL)PYRIDIN 2 YL]BENZYL] 3 PROPYLIMIDAZOLIDINE 2,4 DIONE; 1 [4 [5 FLUORO 6 [(3 FLUOROPIPERIDIN 1 YL)METHYL]PYRIDIN 2 YL]BENZYL] 3 ISOBUTYLIMIDAZOLIDINE 2,4 DIONE; 1 [4 [5 FLUORO 6 [(3 METHYLPIPERIDIN 1 YL)METHYL]PYRIDIN 2 YL]BENZYL] 3 ISOBUTYLIMIDAZOLIDINE 2,4 DIONE; 1 [4 [6 (1,1 DIOXO 1LAMBDA6 THIOMORPHOLIN 4 YLMETHYL) 5 FLUOROPYRIDIN 2 YL]BENZYL] 3 ISOBUTYLIMIDAZOLIDINE 2,4 DIONE; 1 [4 [6 (CYCLOHEXYLMETHYL)PYRIDIN 2 YL]BENZYL] 3 ETHYLIMIDAZOLIDINE 2,4 DIONE; 1 [4 [6 (PIPERIDIN 1 YLMETHYL)PYRIDIN 2 YL]BENZYL] 3 (2,2,2 TRIFLUOROETHYL)IMIDAZOLIDINE 2,4 DIONE; 1 [4 [6 (PIPERIDIN 1 YLMETHYL)PYRIDIN 2 YL]BENZYL] 3 PROPYLIMIDAZOLIDINE 2,4 DIONE; 1 [4 [6 [(1,1 DIOXO 1LAMBDA6 THIOMORPHOLIN 4 YL)METHYL]PYRIDIN 2 YL]BENZYL] 3 ISOBUTYLIMIDAZOLIDINE 2,4 DIONE; 1 [4 [6 [(3 FLUOROPIPERIDIN 1 YL)METHYL]PYRIDIN 2 YL]BENZYL] 3 ISOBUTYLIMIDAZOLIDINE 2,4 DIONE; 1 [4 [6 [(3,3 DIFLUOROPIPERIDIN 1 YL)METHYL] 5 FLUOROPYRIDIN 2 YL]BENZYL] 3 ISOBUTYLIMIDAZOLIDINE 2,4 DIONE; 1 [4 [6 [(3,3 DIFLUOROPIPERIDIN 1 YL)METHYL]PYRIDIN 2 YL]BENZYL] 3 ISOBUTYLIMIDAZOLIDINE 2,4 DIONE; 3 (2,2 DIFLUOROETHYL) 1 [4 [5 FLUORO 6 (PIPERIDIN 1 YLMETHYL)PYRIDIN 2 YL]BENZYL]IMIDAZOLIDINE 2,4 DIONE; 3 (2,2 DIFLUOROETHYL) 1 [4 [6 (PIPERIDIN 1 YLMETHYL)PYRIDIN 2 YL]BENZYL]IMIDAZOLIDINE 2,4 DIONE; 3 (CYCLOBUTYLMETHYL) 1 [4 [5 FLUORO 6 (PIPERIDIN 1 YLMETHYL)PYRIDIN 2 YL]BENZYL]IMIDAZOLIDINE 2,4 DIONE; 3 (CYCLOPROPYLMETHYL) 1 [4 [5 FLUORO 6 (PIPERIDIN 1 YLMETHYL)PYRIDIN 2 YL]BENZYL]IMIDAZOLIDINE 2,4 DIONE; 3 (CYCLOPROPYLMETHYL) 1 [4 [6 (PIPERIDIN 1 YLMETHYL)PYRIDIN 2 YL]BENZYL]IMIDAZOLIDINE 2,4 DIONE; 3 CYCLOBUTYL 1 [4 [6 (PIPERIDIN 1 YLMETHYL)PYRIDIN 2 YL]BENZYL]IMIDAZOLIDINE 2,4 DIONE; 3 CYCLOPROPYL 1 [4 [5 FLUORO 6 (PIPERIDIN 1 YLMETHYL)PYRIDIN 2 YL]BENZYL]IMIDAZOLIDINE 2,4 DIONE; 3 CYCLOPROPYL 1 [4 [6 (1,1 DIOXO 1LAMBDA6 THIOMORPHOLIN 4 YLMETHYL) 5 FLUOROPYRIDIN 2 YL]BENZYL]IMIDAZOLIDINE 2,4 DIONE; 3 CYCLOPROPYL 1 [4 [6 (PIPERIDIN 1 YLMETHYL)PYRIDIN 2 YL]BENZYL]IMIDAZOLIDINE 2,4 DIONE; 3 ETHYL 1 [4 [5 FLUORO 6 (PIPERIDIN 1 YLMETHYL)PYRIDIN 2 YL]BENZYL]IMIDAZOLIDINE 2,4 DIONE; 3 ETHYL 1 [4 [6 (PIPERIDIN 1 YLMETHYL)PYRIDIN 2 YL]BENZYL]IMIDAZOLIDINE 2,4 DIONE; 3 ISOBUTYL 1 [4 [6 (PIPERIDIN 1 YLMETHYL)PYRIDIN 2 YL]BENZYL]IMIDAZOLIDINE 2,4 DIONE; 3 ISOBUTYL 1 [4 [6 [(3 METHYLPIPERIDIN 1 YL)METHYL]PYRIDIN 2 YL]BENZYL]IMIDAZOLIDINE 2,4 DIONE; 3 ISOPROPYL 1 [4 [6 (PIPERIDIN 1 YLMETHYL)PYRIDIN 2 YL]BENZYL]IMIDAZOLIDINE 2,4 DIONE; 3 METHYL 1 [4 [6 (PIPERIDIN 1 YLMETHYL)PYRIDIN 2 YL]BENZYL]IMIDAZOLIDINE 2,4 DIONE; CANNABINOID 2 RECEPTOR AGONIST; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CONTROLLED STUDY; DRUG ACTIVITY; DRUG BIOAVAILABILITY; DRUG IDENTIFICATION; DRUG SYNTHESIS; HUMAN; HUMAN CELL; LIPOPHILICITY; MALE; NEUROPATHIC PAIN; NONHUMAN; PHYSICOCHEMICAL MODEL; RAT;

ADMINISTRATION, ORAL; ANALGESICS; ANIMALS; CACO-2 CELLS; CELL MEMBRANE PERMEABILITY; CHO CELLS; CRICETINAE; CRICETULUS; CYCLIC AMP; CYCLIC S-OXIDES; ETHER-A-GO-GO POTASSIUM CHANNELS; HEK293 CELLS; HUMANS; HYDANTOINS; MALE; MICROSOMES, LIVER; NEURALGIA; RATS; RATS, WISTAR; RECEPTOR, CANNABINOID, CB2; SPINAL NERVES; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 80054917398     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm200916p     Document Type: Article

References (30)

1. Vranken, J. H. Mechanisms and treatment of neuropathic pain Cent. Nerv. Syst. Agents Med. Chem. 2009, 9 (1) 71-78
2. Jensen, T. S.; Gottrup, H.; Sindrup, S. H.; Bach, F. W. The clinical picture of neuropathic pain Eur. J. Pharmacol. 2001, 429 (1-3) 1-11 (Pubitemid 33043977)
3. Adams, I. B.; Martin, B. R. Cannabis: pharmacology and toxicology in animals and humans Addiction 1996, 91 (11) 1585-1614 (Pubitemid 26393422)
4. Rice, A. S. Should cannabinoids be used as analgesics for neuropathic pain? Nature Clin. Pract. Neurol. 2008, 4 (12) 654-655
5. Lynch, M. E.; Campbell, F. Cannabinoids for Treatment of Chronic Non-Cancer Pain; a Systematic Review of Randomized Trials. Br. J. Clin. Pharmacol. 2011, doi: 10.1111/j.1365-2125.2011.03970.x.
6. 1 and CB2 Pharmacol Rev. 2010, 62 (4) 588-631
7. Freund, T. F.; Katona, I; Piomelli, D. Role of endogenous cannabinoids in synaptic signaling Physiol. Rev. 2003, 83 (3) 1017-1066 (Pubitemid 36828930)
8. Patel, K. D.; Davison, J. S.; Pittman, Q. J.; Sharkey, K. A. Cannabinoid CB(2) receptors in health and disease Curr. Med. Chem. 2010, 17 (14) 1393-1410
9. Benito, C; Tolón, R. M.; Pazos, M. R.; Núñez, E; Castillo, A. I.; Romero, J. Cannabinoid CB2 receptors in human brain inflammation Br. J. Pharmacol. 2008, 153 (2) 277-285
10. Anand, U; Otto, W. R.; Sanchez-Herrera, D; Facer, P; Yiangou, Y; Korchev, Y; Birch, R; Benham, C; Bountra, C; Chessell, I. P.; Anand, P. Cannabinoid receptor CB2 localisation and agonist-mediated inhibition of capsaicin responses in human sensory neurons Pain 2008, 138 (3) 667-680
11. Anand, P; Whiteside, G; Fowler, C. J.; Hohmann, A. G. Targeting CB2 receptors and the endocannabinoid system for the treatment of pain Brain Res. Rev. 2009, 60 (1) 255-266
12. Guindon, J; Hohmann, A. G. Cannabinoid CB2 receptors: a therapeutic target for the treatment of inflammatory and neuropathic pain Br. J. Pharmacol. 2008, 153 (2) 319-334
13. Whiteside, G. T.; Lee, G. P.; Valenzano, K. J. The role of the cannabinoid CB2 receptor in pain transmission and therapeutic potential of small molecule CB2 receptor agonists Curr. Med. Chem. 2007, 14 (8) 917-36 (Pubitemid 46863619)
14. Racz, I; Nadal, X; Alferink, J; Baños, J. E.; Rehnelt, J; Martín, M; Pintado, B; Gutierrez-Adan, A; Sanguino, E; Manzanares, J; Zimmer, A; Maldonado, R. Crucial role of CB(2) cannabinoid receptor in the regulation of central immune responses during neuropathic pain J. Neurosci. 2008, 28 (46) 12125-12135
15. Racz, I; Nadal, X; Alferink, J; Baños, J. E.; Rehnelt, J; Martín, M; Pintado, B; Gutierrez-Adan, A; Sanguino, E; Bellora, N; Manzanares, J; Zimmer, A; Maldonado, R. Interferon-gamma is a critical modulator of CB(2) cannabinoid receptor signaling during neuropathic pain J. Neurosci. 2008, 28 (46) 12136-12145
16. Thakur, G. A.; Tichkule, R; Bajaj, S; Makriyannis, A. Latest advances in cannabinoid receptor agonists Expert Opin. Ther. Pat. 2009, 19 (12) 1647-1673
17. Worm, K; Dolle, R. E. Simultaneous optimization of potency, selectivity and physicochemical properties for cannabinoid CB(2) ligands Curr. Pharm. Des. 2009, 15 (29) 3345-3366
18. Hanus, L; Breuer, A; Tchilibon, S; Shiloah, S; Goldenberg, D; Horowitz, M; Pertwee, R. G.; Ross, R. A.; Mechoulam, R; Fride, E. HU-308: a specific agonist for CB(2), a peripheral cannabinoid receptor Proc. Natl. Acad. Sci. U.S.A. 1999, 96 (25) 14228-14233 (Pubitemid 30000633)
19. Malan, T. P., Jr.; Ibrahim, M. M.; Deng, H; Liu, Q; Mata, H. P.; Vanderah, T; Porreca, F; Makriyannis, A. CB2 cannabinoid receptor-mediated peripheral antinociception Pain 2001, 93 (3) 239-245 (Pubitemid 32763181)
20. Giblin, G. M.; O'Shaughnessy, C. T.; Naylor, A; Mitchell, W. L.; Eatherton, A. J.; Slingsby, B. P.; Rawlings, D. A.; Goldsmith, P; Brown, A. J.; Haslam, C. P.; Clayton, N. M.; Wilson, A. W.; Chessell, I. P.; Wittington, A. R.; Green, R. Discovery of 2-[(2,4-dichlorophenyl)amino]- N -[(tetrahydro-2 H -pyran-4-yl)methyl]-4-(trifluoromethyl)-5-pyrimidinecarboxamide, a selective CB2 receptor agonist for the treatment of inflammatory pain J. Med. Chem. 2007, 50 (11) 2597-2600 (Pubitemid 46896065)
21. Sánchez, C; de Ceballos, M. L.; Gomez del Pulgar, T; Rueda, D; Corbacho, C; Velasco, G; Galve-Roperh, I; Huffman, J. W.; Ramón y Cajal, S; Guzmán, M. Inhibition of glioma growth in vivo by selective activation of the CB(2) cannabinoid receptor Cancer Res. 2001, 61 (15) 5784-5789 (Pubitemid 32769095)
22. Snyders, D. J.; Chaudhary, A. High affinity open channel block by dofetilide of HERG expressed in a human cell line Mol. Pharmacol. 1996, 49, 949-955 (Pubitemid 26181422)
23. Jamieson, C; Moir, E. M.; Rankovic, Z; Wishart, G. Medicinal chemistry of hERG optimizations: highlights and hang-ups J. Med. Chem. 2006, 49 (17) 5029-5046 (Pubitemid 44260200)
24. Kim, S. H.; Chung, J. M. Sympathectomy alleviates mechanical allodynia in an experimental animal model for neuropathy in the rat Neurosci. Lett. 1991, 134 (1) 131-134
25. Ostenfeld, T; Price, J; Albanese, M; Bullman, J; Guillard, F; Meyer, I; Leeson, R; Costantin, C; Ziviani, L; Nocini, P. F.; Milleri, S. A Randomized, Controlled Study to Investigate the Analgesic Efficacy of Single Doses of the Cannabinoid Receptor-2 Agonist GW842166, Ibuprofen or Placebo in Patients With Acute Pain Following Third Molar Tooth Extraction Clin. J. Pain 2011, 27, 668-676
26. Trotter, B. W.; Nanda, K. K.; Burgey, C. S.; Potteiger, C. M.; Deng, J. Z.; Green, A. I.; Hartnett, J. C.; Kett, N. R.; Wu, Z; Henze, D. A.; Della Penna, K; Desai, R; Leitl, M. D.; Lemaire, W; White, R. B.; Yeh, S; Urban, M. O.; Kane, S. A.; Hartman, G. D. Bilodeau MT. Imidazopyridine CB2 agonists: optimization of CB2/CB1 selectivity and implications for in vivo analgesic efficacy Bioorg. Med. Chem. Lett. 2011, 21 (8) 2354-2358
27. Manley, P. J.; Zartman, A; Paone, D. V.; Burgey, C. S.; Henze, D. A.; Della Penna, K; Desai, R; Leitl, M. D.; Lemaire, W; White, R. B.; Yeh, S; Urban, M. O.; Kane, S. A.; Hartman, G. D.; Bilodeau, M. T.; Trotter, B. W. Decahydroquinoline amides as highly selective CB2 agonists: role of selectivity on in vivo efficacy in a rodent model of analgesia Bioorg. Med. Chem. Lett. 2011, 21 (8) 2359-2364
28. Ofek, O; Karsak, M; Leclerc, N; Fogel, M; Frenkel, B; Wright, K; Tam, J; Attar-Namdar, M; Kram, V; Shohami, E; Mechoulam, R; Zimmer, A; Bab, I Peripheral cannabinoid receptor, CB2, regulates bone mass Proc. Natl. Acad. Sci. U.S.A. 2006, 103 (3) 696-701 (Pubitemid 43153088)
29. Lombardo, F; Shalaeva, M. Y.; Tupper, K. A.; Gao, F. ElogD(oct): a tool for lipophilicity determination in drug discovery. 2. Basic and neutral compounds J. Med. Chem. 2001, 44 (15) 2490-2497 (Pubitemid 32852170)
30. Kaptein, A; Oubrie, A; de Zwart, E; Hoogenboom, N; de Wit, J; van de Kar, B; van Hoek, M; Vogel, G; de Kimpe, V; Schultz-Fademrecht, C; Borsboom, J; van Zeeland, M; Versteegh, J; Kazemier, B; de Roos, J; Wijnands, F; Dulos, J; Jaeger, M; Leandro-Garcia, P; Barf, T. Discovery of selective and orally available spiro-3-piperidyl ATP-competitive MK2 inhibitors Bioorg. Med. Chem. Lett. 2011, 21 (12) 3823-3827