1-Aryl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamide: An effective scaffold for the design of either CB 1 or CB 2 receptor ligands

European Journal of Medicinal Chemistry

Volumn 46, Issue 11, 2011, Pages 5641-5653

  Piscitelli, Francesco ^a   Ligresti, Alessia ^b   La Regina, Giuseppe ^a   Gatti, Valerio ^a   Brizzi, Antonella ^c   Pasquini, Serena ^c   Allar, Marco ^b   Carai, Mauro Antonio Maria ^b   Novellino, Ettore ^d   Colombo, Giancarlo ^b   Di Marzo, Vincenzo ^b   Corelli, Federico ^c   Silvestri, Romano ^a  

^a SAPIENZA UNIVERSITY OF ROME   (Italy)

^b CNR   (Italy)

^c UNIVERSITY OF SIENA   (Italy)

^d UNIVERSITY OF NAPLES FEDERICO II   (Italy)

Author keywords

Cannabinoid; Human recombinant CB receptor type 1; Pharmacological studies; Pyrrole bioisosteres; Structure activity relationships

Indexed keywords

1 (2,4 DICHLOROPHENYL) 5 (4 IODOPHENYL) 4 METHYL N (1 PIPERIDYL) 1H PYRAZOLE 3 CARBOXAMIDE; 5 (2 CHLORO 1H PYRROL 1 YL) N (3,4 DICHLOROBENZYL) 1 (2,4 DICHLOROPHENYL) 4 METHYL 1H PYRAZOLE 3 CARBOXAMIDE; 5 (2 CHLORO 1H PYRROL 1 YL) N (3,4 DICHLOROBENZYL) 1 (3,4 DICHLOROPHENYL) 4 METHYL 1H PYRAZOLE 3 CARBOXAMIDE; 5 (2 CHLORO 1H PYRROL 1 YL) N CYCLOHEXYL 1 (2,4 DICHLOROPHENYL) 4 METHYL 1H PYRAZOLE 3 CARBOXAMIDE; 5 (2 CHLORO 1H PYRROL 1 YL) N CYCLOHEXYL 1 (3,4 DICHLOROPHENYL) 4 METHYL 1H PYRAZOLE 3 CARBOXAMIDE; 5 (2,5 DICHLORO 1H PYRROL 1 YL) N (3,4 DICHLOROBENZYL) 1 (2,4 DICHLOROPHENYL) 4 METHYL 1H PYRAZOLE 3 CARBOXAMIDE; 5 (2,5 DICHLORO 1H PYRROL 1 YL) N (3,4 DICHLOROBENZYL) 1 (3,4 DICHLOROPHENYL) 4 METHYL 1H PYRAZOLE 3 CARBOXAMIDE; AMIDE; CANNABINOID 1 RECEPTOR; CANNABINOID 2 RECEPTOR; N (3,4 DICHLOROBENZYL) 1 (2,4 DICHLOROPHENYL) 4 ETHYL 5 (1H PYRROL 1 YL) 1H PYRAZOLE 3 CARBOXAMIDE; N (3,4 DICHLOROBENZYL) 1 (2,4 DICHLOROPHENYL) 4 METHYL 5 (4,5,6,7 TETRAHYDROISOINDOL 2 YL) 1H PYRAZOLE 3 CARBOXAMIDE; N (3,4 DICHLOROBENZYL) 1 (2,4 DICHLOROPHENYL) 5 (2,5 DIMETHYL 1H PYRROL 1 YL) 4 ETHYL 1H PYRAZOLE 3 CARBOXAMIDE; N (3,4 DICHLOROBENZYL) 1 (3,4 DICHLOROPHENYL) 4 ETHYL 5 (1H PYRROL 1 YL) 1H PYRAZOLE 3 CARBOXAMIDE; N (3,4 DICHLOROBENZYL) 1 (3,4 DICHLOROPHENYL) 5 (2,5 DIETHYL 1H PYRROL 1 YL) 4 METHYL 1H PYRAZOLE 3 CARBOXAMIDE; N (3,4 DICHLOROBENZYL) 1 (3,4 DICHLOROPHENYL) 5 (2,5 DIMETHYL 1H PYRROL 1 YL) 4 ETHYL 1H PYRAZOLE 3 CARBOXAMIDE; N CYCLOHEXYL 1 (2,4 DICHLOROPHENYL) 4 ETHYL 5 (1H PYRROL 1 YL) 1H PYRAZOLE 3 CARBOXAMIDE; N CYCLOHEXYL 1 (2,4 DICHLOROPHENYL) 5 (2,5 DIMETHYL 1H PYRROL 1 YL) 4 ETHYL 1H PYRAZOLE 3 CARBOXAMIDE; N CYCLOHEXYL 1 (3,4 DICHLOROPHENYL) 4 ETHYL 5 (1H PYRROL 1 YL) 1H PYRAZOLE 3 CARBOXAMIDE; N CYCLOHEXYL 1 (3,4 DICHLOROPHENYL) 4 METHYL 5 (4,5,6,7 TETRAHYDROISOINDOL 2 YL) 1H PYRAZOLE 3 CARBOXAMIDE; N CYCLOHEXYL 1 (3,4 DICHLOROPHENYL) 5 (2,5 DIETHYL 1H PYRROL 1 YL) 4 METHYL 1H PYRAZOLE 3 CARBOXAMIDE; N CYCLOHEXYL 1 (3,4 DICHLOROPHENYL) 5 (2,5 DIMETHYL 1H PYRROL 1 YL) 4 ETHYL 1H PYRAZOLE 3 CARBOXAMIDE; N CYCLOHEXYL 5 (2,5 DICHLORO 1H PYRROL 1 YL) 1 (2,4 DICHLOROPHENYL) 4 METHYL 1H PYRAZOLE 3 CARBOXAMIDE; N CYCLOHEXYL 5 (2,5 DICHLORO 1H PYRROL 1 YL) 1 (3,4 DICHLOROPHENYL) 4 METHYL 1H PYRAZOLE 3 CARBOXAMIDE; RIMONABANT; SUCROSE; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ARTICLE; BINDING AFFINITY; CONTROLLED STUDY; DRUG DESIGN; DRUG RECEPTOR BINDING; DRUG SELECTIVITY; DRUG STRUCTURE; FOOD INTAKE; MALE; NONHUMAN; PROTON NUCLEAR MAGNETIC RESONANCE; RAT;

ANIMALS; DRUG DESIGN; EATING; HUMANS; LIGANDS; MALE; PYRAZOLES; RATS; RATS, WISTAR; RECEPTOR, CANNABINOID, CB1; RECEPTOR, CANNABINOID, CB2; SUBSTRATE SPECIFICITY;

EID: 80054960004     PISSN: 02235234     EISSN: 17683254     Source Type: Journal    
DOI: 10.1016/j.ejmech.2011.09.037     Document Type: Article

References (42)

1. V. Di Marzo Targeting the endocannabinoid system: to enhance or reduce? Nat. Rev. Drug Discov 7 2008 438 455 (Pubitemid 351649182)
2. S. Pavlopoulos, G.A. Thakur, S.P. Nikas, and A. Makriyannis Cannabinoid receptors as therapeutic targets Curr. Pharm. Des. 12 2006 1751 1769
3. L. Bellocchio, G. Mancini, V. Vicennati, R. Pasquali, and U. Pagotto Cannabinoid receptors as therapeutic targets for obesity and metabolic diseases Curr. Opin. Pharmacol. 6 2006 586 591 (Pubitemid 44660950)
4. D.M. Lambert, and C.J. Fowler The endocannabinoid system: drug targets, lead compounds, and potential therapeutic applications J. Med. Chem. 48 2005 5059 5087 (Pubitemid 41113892)
5. R.S. Padwal, and S.R. Majumdar Drug treatments for obesity: orlistat, sibutramine, and rimonabant Lancet 369 2007 71 77 (Pubitemid 46027230)
6. S.A. Doggrell Is rimonabant efficacious and safe in the treatment ofobesity? Expert Opin. Pharmacother. 9 2008 2727 2731
7. D.R. Janero, and A. Makriyannis Cannabinoid receptor antagonists: pharmacological opportunities, clinical experience, and translational prognosis Expert Opin. Drug Discov. 14 2009 43 65
8. For example, Taranabant, Otenabant, Ibipinabant and AVE1625 are new CB1 receptor antagonists/inverse agonists which have also been evaluated in clinical studies.
9. 1 cannabinoid receptor-ligand Bioorg. Med. Chem. 18 2010 1149 1162
10. 1antagonists Bioorg. Med. Chem. Lett. 20 2010 26e 30
11. J. Boström, R.I. Olsson, J. Tholander, P.J. Greasley, E. Ryberg, H. Nordberg, S. Hjorth, and L. Cheng Novel thioamide derivatives as neutral CB1 receptor antagonists Bioorg. Med. Chem. Lett. 20 2010 479 482
12. J.S. Debenham, C.B. Madsen-Duggan, R.B. Toupence, T.F. Walsh, J. Wang, X. Tong, S. Kumar, J. Lao, T.M. Fong, J.C. Xiao, C.R.-R.C. Huang, C.-P. Shen, Y. Feng, D.J. Marsh, D.S. Stribling, L.P. Shearman, A.M. Strack, and M.T. Goulet Furo[2,3-b]pyridine-based cannabinoid-1 receptor inverse agonists: synthesis and biological evaluation. Part 1 Bioorg. Med. Chem. Lett. 20 2010 1448 1452
13. 1 receptor antagonism J. Med. Chem. 53 2010 1338 1346
14. H. Pettersson, A. Bülow, F. Ek, J. Jensen, L.K. Ottesen, A. Fejzic, J.-N. Ma, A.L. Del Tredici, E.A. Currier, L.R. Gardell, A. Tabatabaei, D. Craig, K. McFarland, T.R. Ott, F. Piu, E.S. Burstein, and R. Olsson Synthesis and evaluation of dibenzothiazepines: a novel class of selective cannabinoid-1 receptor inverse agonists J. Med. Chem. 52 2009 1975 1982
15. P. Diaz, S.S. Phatak, J. Xu, F. Astruc-Diaz, C.N. Cavasotto, and M. Naguib 6-Methoxy-N-alkyl isatin acylhydrazone derivatives as a novel series of potent selective cannabinoid receptor 2 inverse agonists: design, synthesis, and binding mode prediction J. Med. Chem. 52 2009 433 444
16. G. Szabó, B. Varga, D. Páyer-Lengyel, A. Szemzó, P. Erdélyi, K. Vukics, J. Szikra, E. Hegyi, M. Vastag, B. Kiss, J. Laszy, I. Gyertyán, and J. Fischer Chemical and biological investigation of cyclopropyl containing diaryl-pyrazole-3-carboxamides as novel and potent cannabinoid type 1 receptor antagonists J. Med. Chem. 52 2009 4329 4337
17. J. Lee, K.-S. Song, J. Kang, S.H. Lee, and J. Lee New trends in medicinal chemistry approaches to antiobesity therapy Curr. Top. Med. Chem. 9 2009 564 596
18. W.Y. Leung, T.G. Neil, J.C. Chan, and B. Tomlinson Weight management and current options in pharmacotherapy: orlistat and sibutramine Clin. Ther. 25 2003 58 80 (Pubitemid 36206738)
19. European Medicines Agency recently decided to withdraw sibutramine due to cardiovascular risks.
20. For examples of 1's bioisosteres, see our previous paper (see Ref. [9]).
21. D.A. Griffith, J.R. Hadcock, S.C. Black, P.A. Iredale, P.A. Carpino, P. Da Silva-Jardine, R. Day, J. DiBrino, R.L. Dow, M.S. Landis, R.E. O'Connor, and D.O. Scott Discovery of 1-[9-(4-chlorophenyl)-8-(2-chlorophenyl)-9H-purin-6-yl]- 4-ethylaminopiperidine-4-carboxylic acid amide hydrochloride (CP-945,598), a novel, potent, and selective cannabinoid type 1 receptor antagonist J. Med. Chem. 52 2009 234 237
22. R.L. Dow, P.A. Carpino, J.R. Hadcock, S.C. Black, P.A. Iredale, P. Da Silva-Jardine, S.R. Schneider, E.S. Paight, D.A. Griffith, D.O. Scott, R.E. O'Connor, and C.I. Nduaka 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, bicycliclactam-based cannabinoid-1 receptor antagonist for the treatment of obesity J. Med. Chem. 52 2009 2652 2655
23. J.S. Debenham, C.B. Madsen-Duggan, J. Wang, X. Tong, J. Lao, T.M. Fong, M.-T. Schaeffer, J.C. Xiao, C.C.R.-R. Huang, C.-P. Shen, D.S. Stribling, L.P. Shearman, A.M. Strack, D.E. MacIntyre, J.J. Hale, and T.F. Walsh Pyridopyrimidine based cannabinoid-1 receptor inverse agonists: synthesis and biological evaluation Bioorg. Med. Chem. Lett. 19 2009 2591 2594
24. R. Smith, A.Z. Fathi, S.-E. Brown, S. Choi, J. Fan, S. Jenkins, H.C.E. Kluender, A. Konkar, R. Lavoie, R. Mays, J. Natoli, S.J. O'Connor, A.A. Ortiz, B. Podlogar, C. Taing, S. Tomlinson, T. Tritto, and Z. Zhang Constrained analogs of CB1 antagonists: 1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridine-4-one derivatives Bioorg. Med. Chem. Lett. 17 2007 673 678 (Pubitemid 46108563)
25. Some examples of our studies on pyrrole bioisosteric analogues
26. R. Silvestri, G. La Regina, G. De Martino, M. Artico, O. Befani, M. Palumbo, E. Agostinelli, and P. Turini Simple, potent and selective pyrrole inhibitors of monoamine oxidase type A and type B J. Med. Chem. 46 2003 917 920 (Pubitemid 36423138)
27. R. Silvestri, M. Artico, G. La Regina, G. De Martino, M. La Colla, R. Loddo, and P. LaColla Anti-HIV-1 activity of pyrryl aryl sulfone (PAS) derivatives, synthesis and SAR studies of novel esters and amides at the position 2 of the pyrrole nucleus Farmaco 59 2004 201 210 (Pubitemid 38251617)
28. R. Silvestri, G. Marf, M. Artico, G. La Regina, G. De Martino, A. Lavecchia, E. Novellino, E. Morgante, C. Di Stefano, G. Catalano, G. Filomeni, E. Abruzzese, M.R. Ciriolo, M.A. Russo, S. Amadori, R. Cirilli, F. La Torre, and P. Sinibaldi Salimei Pyrrolo[1,2-b][1,2,5]benzothiadiazepines (PBTDs): a new class of agents endowed with high apoptotic activity in chronic myelogenous leukemia K562 cells and in cells from patients at onset and imatinib-resistant J. Med. Chem 49 2006 5840 5844 (Pubitemid 44423720)
29. R. Silvestri, M.G. Cascio, G. La Regina, F. Piscitelli, A. Lavecchia, A. Brizzi, S. Pasquini, M. Botta, E. Novellino, V. Di Marzo, and F. Corelli Synthesis, cannabinoid receptor affinity, and molecular modeling studies of substituted 1-aryl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamides J. Med. Chem. 51 2008 1560 1576 (Pubitemid 351438840)
30. R. Silvestri, A. Ligresti, G. La Regina, F. Piscitelli, A. Lavecchia, A. Brizzi, S. Pasquini, M. Allar, N. Fantini, M.A.M. Carai, E. Novellino, G. Colombo, V. Di Marzo, and F. Corelli Synthesis, cannabinoid receptor affinity, molecular modeling studies and in vivo pharmacological evaluation of new substituted 1-aryl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamides. 2. Effect of the 3-carboxamide substituent on the affinity and selectivity profile Bioorg. Med. Chem. 17 2009 5549 5564
31. R. Silvestri, A. Ligresti, G. La Regina, F. Piscitelli, V. Gatti, A. Lavecchia, A. Brizzi, S. Pasquini, M. Allar, N. Fantini, M.A.M. Carai, C. Bigogno, M.G. Rozio, R. Sinisi, E. Novellino, G. Colombo, V. Di Marzo, G. Dondio, and F. Corelli Synthesis and biological evaluation of new N-alkyl 1-aryl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamides as cannabinoid receptor ligands Eur. J. Med. Chem. 45 2010 5878 5886
32. A. Brizzi, V. Brizzi, M.G. Cascio, T. Bisogno, R. Siriani, and V. Di Marzo Design, synthesis, and binding studies of new potent ligands of cannabinoid receptors J. Med. Chem. 48 2005 7343 7350 (Pubitemid 41743648)
33. 50) of an enzymatic reaction Biochem. Pharmacol. 22 1973 3099 3108
34. 1) receptors Psychopharmacology 132 1997 104 106 (Pubitemid 27303746)
35. 1 receptor antagonists in reducing food intake and body weight: preclinical and clinical data CNS Drug Rev. 12 2006 91 99 (Pubitemid 44300378)
36. G. Colombo, R. Agabio, G. Diaz, C. Lobina, R. Reali, and G.L. Gessa Appetite suppression and weight loss after the cannabinoid antagonist SR 141716 Life Sci. 63 1998 PL113 PL117
37. G.L. Gessa, A. Orr, P. Lai, P. Maccioni, R. Lecca, C. Lobina, M.A.M. Carai, and G. Colombo Lack of tolerance to the suppressing effect of rimonabant on chocolate intake in rats Psychopharmacology 185 2006 248 254 (Pubitemid 43363621)
38. 9-tetrahydrocannabinol, anandamide, 2-arachidonoyl glycerol and SR141716 Psychopharmacology 165 2003 370 377 (Pubitemid 36223078)
39. 1 receptor antagonist, rimonabant, of the reinforcing and motivational properties of a chocolate-flavoured beverage in rats Behav. Pharmacol. 19 2008 197 209 (Pubitemid 351670400)
40. J. Simiand, M. Keane, P.E. Keane, and P. Soubrie SR 141716, a CB1 cannabinoid receptor antagonist, selectively reduces sweet food intake in marmoset Behav. Pharmacol. 9 1998 179 181 (Pubitemid 28186515)
41. K.S. Sink, P.J. McLaughlin, J.A. Wood, C. Brown, P. Fan, V.K. Vemuri, Y. Peng, T. Olszewska, G.A. Thakur, A. Makriyannis, L.A. Parker, and J.D. Salamone 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 33 2008 946 955 (Pubitemid 351252707)
42. 1 receptor inverse agonists and neutral antagonists: effects on food intake, food-reinforced behavior and food aversions Physiol. Behav. 91 2007 383 388 (Pubitemid 47016540)