Diphenyl purine derivatives as peripherally selective cannabinoid receptor 1 antagonists

Journal of Medicinal Chemistry

Volumn 55, Issue 22, 2012, Pages 10022-10032

  Fulp, Alan ^a   Bortoff, Katherine ^a   Zhang, Yanan ^a   Seltzman, Herbert ^a   Mathews, James ^a   Snyder, Rodney ^a   Fennell, Tim ^a   Maitra, Rangan ^a  

^a RTI INTERNATIONAL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

(3) 3 [[8 (2 CHLOROPHENYL) 9 (4 CHLOROPHENYL) 9H PURIN 6 YL] AMINO] N ETHYLPIPERIDINE 1 CARBOXAMIDE; 1 [(3) 3 [[8 (2 CHLOROPHENYL) 9 (4 CHLOROPHENYL) 9H PURIN 6 YL] AMINO]PIPERIDIN 1 YL]ETHAN 1 ONE; 1 [1 [8 (2 CHLOROPHENYL) 9 (4 CHLOROPHENYL) 9H PURIN 6 YL] 4 PHENYLPIPERIDIN 4 YL] 3 (PROPAN 2 YL)UREA; 1 [1 [8 (2 CHLOROPHENYL) 9 (4 CHLOROPHENYL) 9H PURIN 6 YL] 4 PHENYLPIPERIDIN 4 YL] 3 ETHYLUREA; 1 [1 [8 (2 CHLOROPHENYL) 9 (4 CHLOROPHENYL) 9H PURIN 6 YL] 4 PHENYLPIPERIDIN 4 YL] 3 PROPYLUREA; 1 [1 [8 (2 CHLOROPHENYL) 9 (4 CHLOROPHENYL) 9H PURIN 6 YL]PIPERIDIN 4 YL] 3 (PROPAN 2 YL)UREA; 1 [1 [8 (2 CHLOROPHENYL) 9 (4 CHLOROPHENYL) 9H PURIN 6 YL]PIPERIDIN 4 YL] 3 ETHYLUREA; 1 [8 (2 CHLOROPHENYL) 9 (4 CHLOROPHENYL) 9H PURIN 6 YL] 4 PHENYLPIPERIDIN 4 AMINE; 1 [8 (2 CHLOROPHENYL) 9 (4 CHLOROPHENYL) 9H PURIN 6 YL] 4 PHENYLPIPERIDINE 4 CARBOXAMIDE; 1 [8 (2 CHLOROPHENYL) 9 (4 CHLOROPHENYL) 9H PURIN 6 YL]PIPERIDIN 4 AMINE; 3 [1 [8 (2 CHLOROPHENYL) 9 (4 CHLOROPHENYL) 9H PURIN 6 YL] 4 PHENYLPIPERIDIN 4 YL] 1 CYCLOHEXYLUREA; 3 BUTYL 1 [1 [8 (2-CHLOROPHENYL) 9 (4 CHLOROPHENYL) 9H PURIN 6 YL] 4 PHENYLPIPERIDIN 4 YL]UREA; 3 TERT BUTYL 1 [1 [8 (2 CHLOROPHENYL) 9 (4 CHLOROPHENYL) 9H PURIN 6 YL] 4 PHENYLPIPERIDIN 4 YL]UREA; 4 [[8 (2 CHLOROPHENYL) 9 (4 CHLOROPHENYL) 9H PURIN 6 YL]AMINO] N (PROPAN 2 YL)PIPERIDINE 1 CARBOXAMIDE; 4 [[8 (2 CHLOROPHENYL) 9 (4 CHLOROPHENYL) 9H PURIN 6 YL]AMINO] N ETHYLPIPERIDINE 1 CARBOXAMIDE; 4 [[8 (2 CHLOROPHENYL) 9 (4 CHLOROPHENYL) 9H PURIN 6 YL]AMINO] N PROPYLPIPERIDINE 1 CARBOXAMIDE; 8 (2 CHLOROPHENYL) 9 (4 CHLOROPHENYL) N (1 METHANESULFONYLPIPERIDIN 4 YL) 9H PURIN 6 AMINE; 8 (2 CHLOROPHENYL) 9 (4 CHLOROPHENYL) N (PIPERIDIN 4 YL) 9H PURIN 6 AMINE; 8 (2 CHLOROPHENYL) 9 (4 CHLOROPHENYL) N [(3) 1 METHANESULFONYLPIPERIDIN 3 YL] 9H PURIN 6 AMINE; 8 (2 CHLOROPHENYL) 9 (4 CHLOROPHENYL) N [(3) PIPERIDIN 3 YL] 9H PURIN 6 AMINE; CANNABINOID 1 RECEPTOR ANTAGONIST; ETHYL 2 [[[1 [8 (2 CHLOROPHENYL) 9 (4 CHLOROPHENYL) 9H PURIN 6 YL] 4 PHENYLPIPERIDIN 4 YL]CARBAMOYL]AMINO]ACETATE; N [1 [8 (2 CHLOROPHENYL) 9 (4 CHLOROPHENYL) 9H PURIN 6 YL] 4 PHENYLPIPERIDIN 4 YL]METHANESULFONAMIDE; N BUTYL 4 [[8 (2 CHLOROPHENYL) 9 (4 CHLOROPHENYL) 9H PURIN 6 YL]AMINO]PIPERIDINE 1 CARBOXAMIDE; PURINE DERIVATIVE; TERT BUTYL (3) 3 [[8 (2 CHLOROPHENYL) 9 (4 CHLOROPHENYL) 9H PURIN 6 YL]AMINO]PIPERIDINE 1 CARBOXYLATE; TERT BUTYL 4 [[8 (2 CHLOROPHENYL) 9 (4 CHLOROPHENYL) 9H PURIN 6 YL]AMINO]PIPERIDINE 1 CARBOXYLATE; TERT BUTYL N [1 [8 (2 CHLOROPHENYL) 9 (4 CHLOROPHENYL) 9H PURIN 6 YL] 4 PHENYLPIPERIDIN 4 YL]CARBAMATE; TERT BUTYL N [1 [8 (2 CHLOROPHENYL) 9 (4 CHLOROPHENYL) 9H PURIN 6 YL]PIPERIDIN 4 YL]CARBAMATE; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ARTICLE; DRUG ABSORPTION; DRUG ANTAGONISM; DRUG PENETRATION; DRUG POTENCY; DRUG SYNTHESIS; FUNCTIONAL ASSESSMENT; NONHUMAN; RAT;

ANIMALS; BIPHENYL COMPOUNDS; BRAIN; CALCIUM; CANNABINOID RECEPTOR ANTAGONISTS; CELL MEMBRANE PERMEABILITY; CELLS, CULTURED; DOGS; DRUG DESIGN; MALE; MODELS, MOLECULAR; MOLECULAR STRUCTURE; P-GLYCOPROTEIN; PURINES; RADIOLIGAND ASSAY; RATS; RATS, SPRAGUE-DAWLEY; RECEPTOR, CANNABINOID, CB1; STRUCTURE-ACTIVITY RELATIONSHIP; SULFONAMIDES;

EID: 84870037980     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm301181r     Document Type: Article

References (27)

1. Reggio, P. H. Endocannabinoid binding to the cannabinoid receptors: what is known and what remains unknown Curr. Med. Chem. 2010, 17, 1468-1486
2. Pacher, P.; Batkai, S.; Kunos, G. The endocannabinoid system as an emerging target of pharmacotherapy Pharmacol. Rev. 2006, 58, 389-462
3. Mouslech, Z.; Valla, V. Endocannabinoid system: An overview of its potential in current medical practice Neuroendocrinol. Lett. 2009, 30, 153-179
4. Demuth, D. G.; Molleman, A. Cannabinoid signalling Life Sci. 2006, 78, 549-563
5. De Vries, T. J.; Schoffelmeer, A. N. Cannabinoid CB1 receptors control conditioned drug seeking Trends Pharmacol. Sci. 2005, 26, 420-426
6. Le Foll, B.; Goldberg, S. R. Cannabinoid CB1 receptor antagonists as promising new medications for drug dependence J. Pharmacol. Exp. Ther. 2005, 312, 875-883
7. Wierzbicki, A. S. Rimonabant: endocannabinoid inhibition for the metabolic syndrome Int. J. Clin. Pract. 2006, 60, 1697-1706
8. Janero, D. R.; Makriyannis, A. Cannabinoid receptor antagonists: pharmacological opportunities, clinical experience, and translational prognosis Expert Opin. Emerging Drugs 2009, 14, 43-65
9. Janero, D. R.; Makriyannis, A. Cannabinoid receptor antagonists: pharmacological opportunities, clinical experience, and translational prognosis Expert Opin. Emerging Drugs 2009, 14, 43-65
10. Di Marzo, V. CB(1) receptor antagonism: biological basis for metabolic effects Drug Discovery Today 2008, 13, 1026-1041
11. Lee, H. K.; Choi, E. B.; Pak, C. S. The Current Status and Future Perspectives of Studies of Cannabinoid Receptor 1 Antagonists as Anti-Obesity Agents Curr. Top. Med. Chem. 2009, 9, 482-503
12. Stein, C.; Schafer, M.; Machelska, H. Attacking pain at its source: new perspectives on opioids Nat. Med. 2003, 9, 1003-1008
13. Tam, J.; Vemuri, V. K.; Liu, J.; Batkai, S.; Mukhopadhyay, B.; Godlewski, G.; Osei-Hyiaman, D.; Ohnuma, S.; Ambudkar, S. V.; Pickel, J.; Makriyannis, A.; Kunos, G. Peripheral CB1 cannabinoid receptor blockade improves cardiometabolic risk in mouse models of obesity. J. Clin. Invest. 2010, 120, 2953. Corrigendum: J. Clin. Invest. 2010, 120, 3735-3735.
14. Tarzia, G.; LoVerme, J.; Duranti, A.; Tontini, A.; Spadoni, G.; Mor, M.; Rivara, S.; Stella, N.; Xu, C.; Piomelli, D. Synthesis and characterization of a peripherally restricted CB(1) cannabinoid antagonist, URB447, that reduces feeding and body-weight gain in mice Bioorg. Med. Chem. Lett. 2009, 19, 639-643
15. Barth, F.; Hortala, L.; Rinaldi-Carmona, M.; Congy, C.; Boulu, L.; Sadoun, F.; Fabre, G.; Finance, O. Rational design of a novel peripherally-restricted, orally active CB(1) cannabinoid antagonist containing a 2,3-diarylpyrrole motif Bioorg. Med. Chem. Lett. 2010, 20, 4573-4577
16. Hogberg, T.; Cooper, M.; Receveur, J. M.; Bjurling, E.; Norregaard, P. K.; Nielsen, P. A.; Skold, N. Exploring SAR features in diverse library of 4-cyanomethyl-pyrazole-3-carboxamides suitable for further elaborations as CB1 antagonists Bioorg. Med. Chem. Lett. 2010, 20, 26-30
17. Hogberg, T.; Receveur, J. M.; Murray, A.; Linget, J. M.; Norregaard, P. K.; Cooper, M.; Bjurling, E.; Nielsen, P. A. Conversion of 4-cyanomethyl- pyrazole-3-carboxamides into CB1 antagonists with lowered propensity to pass the blood-brain-barrier Bioorg. Med. Chem. Lett. 2010, 20, 453-457
18. Sasmal, P. K.; Reddy, D. S.; Talwar, R.; Venkatesham, B.; Balasubrahmanyam, D.; Kannan, M.; Srinivas, P.; Kumar, K. S.; Devi, B. N.; Jadhav, V. P.; Khan, S. K.; Mohan, P.; Chaudhury, H.; Bhuniya, D.; Iqbal, J.; Chakrabarti, R. Novel pyrazole-3-carboxamide derivatives as cannabinoid-1 (CB1) antagonists: Journey from non-polar to polar amides Bioorg. Med. Chem. Lett. 2011, 21, 562-568
19. Chen, R. Z.; Frassetto, A.; Lao, J. Z.; Huang, R. R. C.; Xiao, J. C.; Clements, M. J.; Walsh, T. F.; Hale, J. J.; Wang, J. Y.; Tong, X. C.; Fong, T. M. Pharmacological evaluation of LH-21, a newly discovered molecule that binds to cannabinoid CB1 receptor Eur. J. Pharmacol. 2008, 584, 338-342
20. Fulp, A.; Bortoff, K.; Zhang, Y.; Seltzman, H.; Snyder, R.; Maitra, R. Towards rational design of cannabinoid receptor 1 (CB1) antagonists for peripheral selectivity Bioorg. Med. Chem. Lett. 2011, 21, 5711-5714
21. Clark, D. E.; Pickett, S. D. Computational methods for the prediction of drug-likeness Drug Discovery Today 2000, 5, 49-58
22. Fulp, A.; Bortoff, K.; Seltzman, H.; Zhang, Y.; Mathews, J.; Snyder, R.; Fennell, T.; Maitra, R. Design and synthesis of cannabinoid receptor 1 antagonists for peripheral selectivity J. Med. Chem. 2012, 55, 2820-2834
23. Griffith, D. A.; Hadcock, J. R.; Black, S. C.; Iredale, P. A.; Carpino, P. A.; DaSilva-Jardine, P.; Day, R.; DiBrino, J.; Dow, R. L.; Landis, M. S.; O'Connor, R. E.; Scott, D. O. Discovery of 1-[9-(4-chlorophenyl)-8-(2- chlorophenyl)-9H-purin-6-yl]-4-ethylaminopiperi dine-4-carboxylic acid amide hydrochloride (CP-945,598), a novel, potent, and selective cannabinoid type 1 receptor antagonist J. Med. Chem. 2009, 52, 234-237
24. Zhang, Y.; Gilliam, A.; Maitra, R.; Damaj, M. I.; Tajuba, J. M.; Seltzman, H. H.; Thomas, B. F. Synthesis and biological evaluation of bivalent ligands for the cannabinoid 1 receptor J. Med. Chem. 2010, 53, 7048-7060
25. Doran, A.; Obach, R. S.; Smith, B. J.; Hosea, N. A.; Becker, S.; Callegari, E.; Chen, C.; Chen, X.; Choo, E.; Cianfrogna, J.; Cox, L. M.; Gibbs, J. P.; Gibbs, M. A.; Hatch, H.; Hop, C. E.; Kasman, I. N.; Laperle, J.; Liu, J.; Liu, X.; Logman, M.; Maclin, D.; Nedza, F. M.; Nelson, F.; Olson, E.; Rahematpura, S.; Raunig, D.; Rogers, S.; Schmidt, K.; Spracklin, D. K.; Szewc, M.; Troutman, M.; Tseng, E.; Tu, M.; Van Deusen, J. W.; Venkatakrishnan, K.; Walens, G.; Wang, E. Q.; Wong, D.; Yasgar, A. S.; Zhang, C. The impact of P-glycoprotein on the disposition of drugs targeted for indications of the central nervous system: evaluation using the MDR1A/1B knockout mouse model Drug Metab. Dispos. 2005, 33, 165-174
26. Polli, J. W.; Olson, K. L.; Chism, J. P.; John-Williams, L. S.; Yeager, R. L.; Woodard, S. M.; Otto, V.; Castellino, S.; Demby, V. E. An unexpected synergist role of P-glycoprotein and breast cancer resistance protein on the central nervous system penetration of the tyrosine kinase inhibitor lapatinib (N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methylsulfonyl)ethy l]amino}methyl)-2-furyl]-4-quinazolinamine; GW572016) Drug Metab. Dispos. 2009, 37, 439-442
27. Hadcock, J. R.; Griffith, D. A.; Iredale, P. A.; Carpino, P. A.; Dow, R. L.; Black, S. C.; O'Connor, R.; Gautreau, D.; Lizano, J. S.; Ward, K.; Hargrove, D. M.; Kelly-Sullivan, D.; Scott, D. O. In vitro and in vivo pharmacology of CP-945,598, a potent and selective cannabinoid CB(1) receptor antagonist for the management of obesity Biochem. Biophys. Res. Commun. 2010, 394, 366-371