A new perspective of cannabinoid 1 receptor antagonists: Approaches toward peripheral CB1R blockers without crossing the blood-brain barrier

Current Topics in Medicinal Chemistry

Volumn 11, Issue 12, 2011, Pages 1421-1429

  Wu, Yen Ku ^a   Yeh, Ching Fang ^b   Ly, Tai Wei ^c   Hung, Ming Shiu ^b  

^a UNIVERSITY OF ALBERTA   (Canada)

^b NATIONAL HEALTH RESEARCH INSTITUTES   (Taiwan)

^c Axikin Pharmaceuticals Inc   (United States)

Author keywords

Cannabinoid 1 receptor; Metabolic disorders; Peripheral antagonists; SR141716A

Indexed keywords

4 AMINOBUTYRIC ACID A RECEPTOR; ADIPONECTIN; AM 654; AM 6545; ANTIOBESITY AGENT; BPR 912; CANNABINOID 1 RECEPTOR ANTAGONIST; HIGH DENSITY LIPOPROTEIN CHOLESTEROL; OTENABANT; RIMONABANT; SURINABANT; TARANABANT; TM 38837; TRIACYLGLYCEROL; UNCLASSIFIED DRUG; URB 447;

BLOOD BRAIN BARRIER; CARDIOVASCULAR RISK; CENTRAL NERVOUS SYSTEM; DIABETES MELLITUS; DRUG BLOOD LEVEL; DRUG EFFICACY; DRUG PENETRATION; DRUG POTENCY; DRUG UPTAKE; FOOD INTAKE; HUMAN; INSULIN RESISTANCE; ISCHEMIC HEART DISEASE; LONG TERM CARE; METABOLIC DISORDER; METABOLIC SYNDROME X; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; OBESITY; REVIEW; STRUCTURE ACTIVITY RELATION;

ANTI-OBESITY AGENTS; BLOOD-BRAIN BARRIER; DIABETES MELLITUS, TYPE 2; FATTY LIVER; HUMANS; METABOLIC DISEASES; METABOLIC SYNDROME X; RECEPTOR, CANNABINOID, CB1; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 79960024748     PISSN: 15680266     EISSN: 18734294     Source Type: Journal    
DOI: 10.2174/156802611795860997     Document Type: Review

References (54)

1. Wilson, R. I.; Nicoll, R. A. Endocannabinoid signaling in the brain. Science, 2002, 296, 678-682.
2. Di Marzo, V.; Després, J.-P. CB1 antagonists for obesity-what lessons have we learned from rimonabant. Nat. Rev. Endocrinol., 2009, 5, 633-638.
3. Buckley, N. E. The peripheral cannabinoid receptor knockout mice: an update. Br. J. Pharmacol., 2008, 153, 309-318.
4. Munro, S.; Thomas, K. L.; Abu-Shaar, M. Molecular characterization of a peripheral receptor for cannabinoids. Nature, 1993, 365, 61-65.
5. Goya, P.; Jagerovic, N. Recent advances in cannabinoid receptor agonists and antagonists. Expert Opin. Ther. Pat., 2000, 10, 1529-1538.
6. Adam, J.; Cowley, P. Recent advances in the cannabinoids. Expert Opin. Ther. Pat., 2002, 12, 1475-1489.
7. Janero, D. R.; Makriyannis, A. Cannabinoid receptor antagonists: pharmacological opportunities, clinical experience, and translational prognosis. Expert Opin. Emerg. Drugs, 2009, 14, 43-65.
8. Bays, H.; Dujovne, C. Pharmacotherapy of obesity: currently marketed and upcoming agents Am. J. Cardiovasc. Drugs, 2002, 2, 245-253.
9. Kaya, A.; Aydi{dotless}n, N.; Topsever, P.; Filiz, M.; Öztürk, A.; Daǧar, A.; Ki{dotless}li{dotless}nç, E.; Ekmekcioglu, C. Efficacy of sibutramine, orlistat and combination therapy on short-term weight management in obese patients. Biomed. Pharmacother., 2004, 58, 582-587.
10. Sjöström, L.; Rissanen, A.; Andersen, T.; Boldrin, M.; Golay, A.; Kopeschaar, H.P.F.; Krempf, M.; for the European Multicentre Orlistat Study Group. Randomised placebo-controlled trial of orlistat for weight loss and prevention of weight regain in obese patients. Lancet, 1998, 352, 167-173.
11. LoVerme, J.; Duranti, A.; Tontini, A.; Spadoni, G.; Mor, M.; Rivara, S.; Stella, N.; Xu, C.; Tarzia, G.; Piomelli, D. Synthesis and characterization of a peripherally restricted CB1 cannabinoid antagonist, URB447, that reduces feeding and body-weight gain in mice. Bioorg. Med. Chem. Lett., 2009, 19, 639-643.
12. Mcelroy, J. F.; Chorvat, R. J. Cannabinoid receptor antagonists/ inverse agonists. International Patent Application Publication, WO 2007/131219, 15 November, 2007.
13. Mcelroy, J.; Chorvat, R. Cannabinoid receptor antagonists/inverse agonists useful for treating obesity. Cannabinoid receptor antagonists/ inverse agonists, WO 2009/033125, 12 March, 2009.
14. Peripheral-acting CB1 antagonists discovered by Jenrin Discovery are reported to play a significant role in the treatment of metabolic disorders with reducing risks of psychiatric adverse effects; Nonbrain penetrant CB1 antagonists from Jenrin Discovery show beneficial effects in treating diabetes and obesity (oral presentation), 26th Annual Scientific Meeting of the Obesity Society, 3-7 October, 2008 (Phoenix, USA).
15. JD-5006, a compound with low brain exposure compared to previously developed CB1 blockers (e.g., 1), may represent a safer alternative for the treatment of liver disease, diabetes and related metabolic disorders, and as exemplified, significant weight loss may not be required for CB1-mediated antidiabetic efficacy. The structure of JD-5006 has not yet been released; Peripheral selective CB1-antagonists as metabolic disorder therapeutics devoid of psychiatric liabilities (oral presentation), 7th International Symposium for Chinese Medicinal Chemists, 1-5 February, 2010 (Taiwan).
16. 7TM Pharma (http://www.7tm.com/); 7TM Pharma announced the selection of a new preclinical development candidate, TM38837, for the treatment of obesity and type II diabetes (http://www.7tm.com/R-D/Metabolic_Disorders/TM38837.aspx; Last accessed: 8 July, 2010); however, the structure of TM38837 has not been released yet.
17. 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.
18. Son, M.-H.; Kim, H. D.; Chae, Y. N.; Kim, M.-K.; Shin, C. Y.; Ahn, G. J.; Choi, S.-h.; Yang, E. K.; Park, K.-J.; Chae, H. W.; Moon, H.-S.; Kim, S.-H.; Shin, Y.-G.; Yoon, S.-H. Peripherally acting CB1-receptor antagonist: the relative importance of central and peripheral CB1 receptors in adiposity control. Int. J. Obes., 2010, 34, 547-556.
19. Fong, T. M.; Heymsfield, S. B. Cannabinoid-1 receptor inverse agonists: current understanding of mechanism of action and unanswered questions. Int. J. Obes., 2009, 33, 947-955.
20. van Gaal, L.; Pi-Sunyer, X.; Després, J.-P.; McCarthy, C.; Scheen, A. Efficacy and safety of rimonabant for improvement of multiple cardiometabolic risk factors in overweight/obese patients: pooled 1-year data from the rimonabant in obesity (RIO) program. Diabetes Care, 2008, 31, S229-S240.
21. Després, J.-P.; Ross, R.; Boka, G.; Alméras, N.; Lemieux, I. Effect of rimonabant on the high-triglyceride/low-HDL-cholesterol dyslipidemia, intraabdominal adiposity, and liver fat: the ADAGIO-lipids trial. Arterioscler., Thromb., Vasc. Biol., 2009, 29, 416-423.
22. Tam, J.; Vemuri, V. K.; Liu J.; Bátkai, 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, 2953-2966.
23. Sink, K. S.; McLaughlin, P. J.; Wood, J. A. T.; Brown, C.; Fan, P.; Vemuri, V. K.; Pang, Y.; Olzewska, T.; Thakur, G. A.; Makriyannis, A.; Parker, L. A.; Salamone, J. D. The novel cannabinoid CB1 receptor neutral antagonist AM4113 suppresses food intake and food-reinforced behavior but does not induce signs of nausea in rats. Neuropsychopharmacology, 2008, 33, 946-955.
24. Noerregaard, P. K.; Fridberg, M.; Elling, C. E. TM38837-a novel second generation peripheral selective CB1 receptor antagonist with efficacy and potency in rodent obesity models equal to brainpenetrant CB1 antagonist rimonabant. 20th annual symposium of the International Cannabinoid Research Society, 2010, 39.
25. Fridberg, M.; Noerregaard, P. K.; Little, P. B.; Cooper, M.; Jensen, N. O.; Elling, C. E. TM38837-a novel second generation peripheral selective CB1 receptor antagonist. Single ascending dose and food effect study of TM38837 in healthy male subjects. 20th annual symposium of the International Cannabinoid Research Society, 2010, P2-26.
26. 7TM Pharma completed a phase I clinical trial and confirmed TM38837 is restricted to the periphery in human (http://www.7tm.com/News.aspx?M=News&PID=42&NewsID=58, news release November 11, 2010).
27. Tseng, S.-L.; Hung, M.-S.; Chang, C.-P.; Song, J.-S.; Tai, C.-L.; Chiu, H.-H.; Hsieh, W.-P.; Lin, Y.; Chung, W.-L.; Kuo, C.-W.; Wu, C.-H.; Chu, C.-M.; Tung, Y.-S.; Chao, Y.-S.; Shia, K.-S. Bioisosteric replacement of the pyrazole 5-aryl Moiety of N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-diclorophenyl)-4-methyl-1Hpyrazole-3-carboxamide (SR141716A). A novel series of alkynylthiophenes as potent and selective canabinoid-1 receptor antagonists J. Med. Chem., 2008, 51, 5397-5412.
28. van de Waterbeemd, H.; Camenisch, G.; Folkers, G.; Chretien, J. R.; Raevsky, O. A. Estimation of blood-brain barrier crossing of drugs using molecular size and shape, and H-bonding descriptors. J. Drug Targeting, 1998, 6, 151-165.
29. Hitchcock, S. A.; Pennington, L. D. Structure-Brain Exposure Relationships. J. Med. Chem., 2006, 49, 7559-7583.
30. Mahar Doan, K. M.; Humphreys, J. E.; Webster, L. O.; Wring, S. A.; Shampie, L. J.; Serabjit-Singh, C. J.; Adkison K. K.; Polli, J. W. Passive permeability and P-glycoprotein-mediated efflux differentiate central nervous system (CNS) and non-CNS marketed drugs. J. Pharmacol. Exp. Ther., 2002, 303, 1029-1037.
31. Shia, K.-S.; Tai, C.-L.; Tsao, J.-P.; Hsieh, W.-P.; Tseng, S.-L.; Hung, M.-S.; Chao, Y.-S. Pyrazole compounds. International Patent Application Publication, WO 2008/060771, 22 May, 2008.
32. Wu, C.-H.; Hung, M.-S.; Song, J.-S.; Yeh, T.-K.; Chou, M.-C.; Chu, C.-M.; Jan, J.-J.; Hsieh, M.-T.; Tseng, S.-L.; Chang, C.-P.; Hsieh, W.-P.; Lin, Y.; Yeh, Y.-N.; Chung, W.-L.; Kuo, C.-W.; Lin, C.-Y.; Shy, H.-S.; Chao, Y.-S.; Shia, K.-S. Discovery of 2-[5-(4-chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-ethyl-1H-pyrazol-3-yl]-1,5,5-trimethyl-1,5-dihydro-imidazol-4-thione (BPR-890) via an active metabolite. A novel, potent and selective cannabinoid-1 receptor inverse agonist with high antiobesity efficacy in DIO mice. J. Med. Chem., 2009, 52, 4496-4510.
33. Hung, M.-S.; Chang, C.-P.; Li, T.-C.; Yeh, T.-K.; Song, J.-S.; Lin, Y.; Wu, C.-H.; Kuo, P.-C.; Amancha P. K.; Wong, Y.-C.; Hsiao, W.-C.; Chao, Y.-S; Shia, K.-S. Discovery of 1-(2,4-dichlorophenyl)-4-ethyl-5-(5-(2-(4-(trifluoromethyl)phenyl) ethynyl) thiophen-2-yl)-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide as a potential peripheral cannabinoid-1 receptor inverse agonist. Chem Med Chem, 2010, 5, 1439-1443.
34. Lin, Y.; Shia, K.-S.; Hsiao, W.-C.; Hsieh, W.-P.; Yeh, T.-K.; Tseng, S.-L.; Hsu, C.-Y.; Chao, Y.-S.; Hung, M.-S. Biphasic suppression of appetite by cannabinoid CB1 receptor antagonists with distinct functional activities. Pharmacol. Res., 2010, 62, 337-343.
35. Cooper, M.; Receveur, J.-M.; Bjurling, E.; Nørregaard, P. K., Nielsen, P. A.; Sköld, N.; Högberg, T. 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.
36. Receveur, J.-M.; Murray, A.; Linget, J.-M.; Nørregaard, P. K.; Cooper, M.; Bjurling, E.; Nielsen, P. A.; Högberg, T. 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.
37. Schinkel, A. H.; Wagenaar, E.; van Deemter, L; Mol, C. A. A. M.; Borst, P. Absence of the mdr1a P-glycoportein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A. J. Clin. Invest., 1995, 96, 1698-1705.
38. Kelder, J.; Grootenhuis, P. D. J.; Bayada, D. M.; Delbressine, L. P. C.; Ploemen, J.-P. Polar molecular surface as a dominating determinant for oral absorption and brain penetration of drugs. Pharm. Res., 1999, 16, 1514-1519.
39. Clark, D. E. In silico prediction of blood-brain barrier permeation. Drug Discov. Today, 2003, 8, 927-933.
40. Bendels, S.; Kansy, M.; Wagner, B.; Huwyler, J. In silico prediction of brain and CSF permeation of small molecules using PLS regression models. Eur. J. Med. Chem., 2008, 43, 1581-1592.
41. Lange, J. H. M.; van der Neut, M. A. W.; Borst, A. J. M; Yildirim, M.; van Stuivenberg, H. H.; van Vliet, B. J.; Kruse, C. G. Probing the cannabinoid CB1/CB2 receptor subtype selectivity limits of 1,2-diarylimidazole-4-carboxamides by fine-tuning their 5-substitution pattern. Bioorg. Med. Chem. Lett., 2010, 20, 2770-2775.
42. Dow, R. L.; Carpino, P. A.; Hadcock, J. R.; Black, S. C.; Iredale, P. A.; DaSilva-Jardine, P.; Schneider, S. R.; Paight, E. S.; Griffith, D. A.; Scott, D. O.; O'Connor, R. E.; Nduaka, C. I. Discovery of 2-(2-chlorophenyl)-3-(4-chlorophenyl)-7-(2,2-difluoropropyl)-6,7-dihydro-2H-pyrazolo[3,4-f][1,4]oxazepin-8-(5H)-one (PF-514273), a novel, bicyclic lactam-based cannabinoid-1 receptor antagonist for the treatment of obesity. J. Med. Chem., 2009, 52, 2652-2655.
43. Hortala, L.; Rinaldi-Carmona, M.; Congy, C.; Boulu, L.; Sadoun, F.; Fabre, G.; Finance, O.; Barth, F. Rational design of a novel peripherally-restricted, orally active CB1 cannabinoid antagonist containing a 2,3-diarylpyrrole motif. Bioorg. Med. Chem. Lett., 2010, 20, 4573-4577.
44. McAllister, S. D.; Rizvi, G.; Anavi-Goffer, S.; Hurst, D. P.; Barnett-Norris, J.; Lynch, D. L.; Reggio, P. H.; Abood, M. E. An aromatic microdomain at the cannabinoid CB1 receptor constitutes an agonist/inverse agonist binding region. J. Med. Chem., 2003, 46, 5139-5152.
45. Boström, J.; Berggren, K.; Elebring, T.; Greasley, P. J.; Wilstermann, M. Scaffold hopping, synthesis and structure-activity relationships of 5,6-diaryl-pyrazine-2-amide derivatives: A novel series of CB1 receptor antagonists. Bioorg. Med. Chem., 2007, 15, 4077-4084.
46. Berggren, A. I. K.; Boström, S. J.; Elebring, S. T.; Fällefors, L.; Wilstermann, J. M.; Greasley, P. 4,5-diarylthiazole derivatives as CB-1 ligands. International Patent Application Publication, WO 2004/058255, 15 July, 2004.
47. Berggren, A. I. K.; Boström, S. J.; Cheng, L.; Elebring, S. T.; Greasly, P.; Nägärd, M.; Wilstermann, J. M.; Terricabras, E. 1,5-diarylpyrrole-3-carboxamide derivatives and their use as cannabinoid receptor modulators. International Patent Application Publication, WO 2004/058249, 15 July, 2004.
48. Finne, P. E.; Meurer, L. C.; Debenham, J. S.; Toupence, R. B.; Walsh, T. F. Substituted 2,3-diphenyl pyridines. International Patent Application Publication, WO 2003/082191, 9 October, 2003.
49. Barth, F.; Martinez, S.; Rinaldi-Carmona, M. Diphenylpyridine derivatives, the preparation thereof, and pharmaceutical compositions containing said derivatives. International Patent Application Publication, WO 2003/084930, 16 October, 2003.
50. Jesberger, M.; Davis, T. P.; Barner, L. Applications of Lawesson's reagent in organic and organometallic syntheses. Synthesis, 2003, 1929-1958.
51. Boström, J.; Olsson, R. I.; Tholander, J.; Greasley, P. J.; Ryberg, E.; Nordberg, H.; Hjorth, S.; Cheng, L. Novel thioamide derivatives as neutral CB1 receptor antagonist. Bioorg. Med. Chem. Lett., 2010, 20, 479-482.
52. Leach, A. G.; Jones, H. D.; Cosgrove, D. A.; Kenny, P. W.; Ruston, L.; MacFaul, P.; Wood, J. M.; Colclough, N.; Law, B. Matched molecular pairs as a guide in the optimization of pharmaceutical properties; a study of aqueous solubility, plasma protein binding and oral exposure. J. Med. Chem., 2006, 49, 6672-6682.
53. Debenham, J. S.; Madsen-Duggan, C. B.; Toupence, R. B.; Walsh, T. F.; Wang, J., Tong, X.; Kumar, S.; Lao, J.; Fong, T. M.; Xiao, J. C.; Huang, C. R.-R. C.; Shen, C.-P.; Feng, Y.; Marsh, D. J.; Stribling, D. S.; Shearman, L. P.; Strack, A. M.; Goulet, M. T. Furo[2,3-b]pyridine-based cannabinoid-1 receptor inverse agonists: synthesis and biological evaluation. Part 1. Bioorg. Med. Chem. Lett., 2010, 20, 1448-1452.
54. Madsen-Duggan, C. B.; Debenham, J. S.; Walsh, T. F.; Yan, L.; Huo, P.; Wang, J.; Tong, X.; Lao, J.; Fong, T. M.; Xiao, J. C.; Huang, C. R.-R. C.; Shen, C.-P.; Stribling, D. S.; Shearman, L. P.; Strack, A. M.; Goulet, M. T.; Hale, J. J. Dihydro-pyrano[2,3-b]pyridines and tetrahydro-1,8-naphthyridines as CB1 receptor inverse agonists: synthesis, SAR and biological evaluation. Bioorg. Med. Chem. Lett., 2010, 20, 3750-3754.