Lead discovery, chemistry optimization, and biological evaluation studies of novel biamide derivatives as CB2 receptor inverse agonists and osteoclast inhibitors

Journal of Medicinal Chemistry

Volumn 55, Issue 22, 2012, Pages 9973-9987

  Yang, Peng ^a   Myint, Kyaw Zeyar ^a,b   Tong, Qin ^a   Feng, Rentian ^a   Cao, Haiping ^a   Almehizia, Abdulrahman A ^a   Alqarni, Mohammed Hamed ^a   Wang, Lirong ^a   Bartlow, Patrick ^a   Gao, Yingdai ^c   Gertsch, Jürg ^d   Teramachi, Jumpei ^e   Kurihara, Noriyoshi ^e   Roodman, Garson David ^e   Cheng, Tao ^c   Xie, Xiang Qun ^a,b  

^a UNIVERSITY OF PITTSBURGH   (United States)

^b UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE   (United States)

^c INSTITUTE OF HEMATOLOGY AND BLOOD DISEASES HOSPITAL   (China)

^d UNIVERSITY OF BERN   (Switzerland)

^e INDIANA UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1 DEOXY 3 (1,1 DIMETHYLBUTYL) DELTA8 TETRAHYDROCANNABINOL; 2 (4 CHLOROPHENYL)ACETAMIDE; 2 PHENYLACETAMIDE; 5 (4 CHLORO 3 METHYLPHENYL) 1 (4 METHYLBENZYL) N (1,3,3 TRIMETHYLBICYCLO[2.2.1]HEPTAN 2 YL) 3 PYRAZOLECARBOXAMIDE; 6 IODO 3 (4 METHOXYBENZOYL) 2 METHYL 1 (2 MORPHOLINOETHYL)INDOLE; AMIDE; BIAMIDE DERIVATIVE; CANNABINOID 2 RECEPTOR; CANNABINOID 2 RECEPTOR AGONIST; GW 842166; JTE 907; LEAD; N',N' (4 TOLYLMETHYLENE)BIS(2 PHENYLACETAMIDE); N',N' (PHENYLMETHYLENE)BIS(2 PHENYLACETAMIDE); N',N' [(2 FLUOROPHENYL)METHYLENE]BIS(2 PHENYLACETAMIDE); N',N' [(4 FLUOROPHENYL)METHYLENE]BIS(2 PHENYLACETAMIDE); N',N' [(4 FLUOROPHENYL)METHYLENE]BIS[2 (4 CHLOROPHENYL)ACETAMIDE]; N',N' [(4 METHOXYPHENYL)METHYLENE]BIS(2 PHENYLACETAMIDE); N',N' [[2 (TRIFLUOROMETHYL)PHENYL]METHYLENE]BIS(2 PHENYLACETAMIDE); N',N' [[4(DIMETHYLAMINO)PHENYL]METHYLENE]BIS(2 PHENYLACETAMIDE); OSTEOCLAST DIFFERENTIATION FACTOR; OSTEOCLAST INHIBITOR; SCH 225336; UNCLASSIFIED DRUG;

ANIMAL CELL; ARTICLE; BINDING AFFINITY; CHEMISTRY; CONTROLLED STUDY; DATA BASE; DRUG CYTOTOXICITY; DRUG DESIGN; DRUG DETERMINATION; DRUG STRUCTURE; DRUG SYNTHESIS; HUMAN; HUMAN CELL; MOUSE; NONHUMAN; OSTEOCLASTOGENESIS; OSTEOPOROSIS; PHARMACOPHORE; STRUCTURE ACTIVITY RELATION;

ALKYLATION; ANIMALS; BENZENEACETAMIDES; BINDING, COMPETITIVE; BONE MARROW; CELL DEATH; CELLS, CULTURED; CHO CELLS; CRICETINAE; CYCLIC AMP; HIGH-THROUGHPUT SCREENING ASSAYS; HUMANS; MODELS, MOLECULAR; MOLECULAR STRUCTURE; OSTEOCLASTS; OSTEOGENESIS; RECEPTOR, CANNABINOID, CB2; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 84870047476     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm301212u     Document Type: Article

References (49)

1. Beltramo, M.; Stella, N.; Calignano, A.; Lin, S. Y.; Makriyannis, A.; Piomelli, D. Functional role of high-affinity anandamide transport, as revealed by selective inhibition Science 1997, 277, 1094-1097
2. Cravatt, B. F.; Giang, D. K.; Mayfield, S. P.; Boger, D. L.; Lerner, R. A.; Gilula, N. B. Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides Nature 1996, 384, 83-87
3. Degenhardt, B. F.; Darmani, N. A.; Johnson, J. C.; Towns, L. C.; Rhodes, D. C.; Trinh, C.; McClanahan, B.; DiMarzo, V. Role of osteopathic manipulative treatment in altering pain biomarkers: a pilot study J. Am. Osteopath. Assoc. 2007, 107, 387-400
4. Matsuda, L. A.; Lolait, S. J.; Brownstein, M. J.; Young, A. C.; Bonner, T. I. Structure of a cannabinoid receptor and functional expression of the cloned cDNA Nature 1990, 346, 561-564
5. Munro, S.; Thomas, K. L.; Abu-Shaar, M. Molecular characterization of a peripheral receptor for cannabinoids Nature 1993, 365, 61-65
6. Sanchez, C.; de Ceballos, M. L.; Gomez del Pulgar, T.; Rueda, D.; Corbacho, C.; Velasco, G.; Galve-Roperh, I.; Huffman, J. W.; Ramon y Cajal, S.; Guzman, M. Inhibition of glioma growth in vivo by selective activation of the CB(2) cannabinoid receptor Cancer Res. 2001, 61, 5784-5789
7. Fernandez-Ruiz, J.; Romero, J.; Velasco, G.; Tolon, R. M.; Ramos, J. A.; Guzman, M. Cannabinoid CB2 receptor: a new target for controlling neural cell survival? Trends Pharmacol. Sci. 2007, 28, 39-45
8. Svizenska, I.; Dubovy, P.; Sulcova, A. Cannabinoid receptors 1 and 2 (CB1 and CB2), their distribution, ligands and functional involvement in nervous system structures - a short review Pharmacol., Biochem. Behav. 2008, 90, 501-511
9. Hohmann, A. G. Spinal and peripheral mechanisms of cannabinoid antinociception: behavioral, neurophysiological and neuroanatomical perspectives Chem. Phys. Lipids 2002, 121, 173-190
10. Karsak, M.; Gaffal, E.; Date, R.; Wang-Eckhardt, L.; Rehnelt, J.; Petrosino, S.; Starowicz, K.; Steuder, R.; Schlicker, E.; Cravatt, B.; Mechoulam, R.; Buettner, R.; Werner, S.; Di Marzo, V.; Tuting, T.; Zimmer, A. Attenuation of allergic contact dermatitis through the endocannabinoid system Science 2007, 316, 1494-1497
11. Palazuelos, J.; Davoust, N.; Julien, B.; Hatterer, E.; Aguado, T.; Mechoulam, R.; Benito, C.; Romero, J.; Silva, A.; Guzman, M.; Nataf, S.; Galve-Roperh, I. The CB2 cannabinoid receptor controls myeloid progenitor trafficking J. Biol. Chem. 2008, 283, 13320-13329
12. Guindon, J.; Hohmann, A. G. The endocannabinoid system and cancer: therapeutic implication Br. J. Pharmacol. 2011, 163, 1447-1463
13. Oesch, S.; Gertsch, J. Cannabinoid receptor ligands as potential anticancer agents - high hopes for new therapies? J. Pharm. Pharmacol. 2009, 61, 839-853
14. Idris, A. I.; Ralston, S. H. Cannabinoids and bone: friend or foe? Calcif. Tissue Int. 2010, 87, 285-297
15. Izzo, A. A.; Camilleri, M. Emerging role of cannabinoids in gastrointestinal and liver diseases: basic and clinical aspects Gut 2008, 57, 1140-1155
16. Munoz-Luque, J.; Ros, J.; Fernandez-Varo, G.; Tugues, S.; Morales-Ruiz, M.; Alvarez, C. E.; Friedman, S. L.; Arroyo, V.; Jimenez, W. Regression of fibrosis after chronic stimulation of cannabinoid CB2 receptor in cirrhotic rats J. Pharmacol. Exp. Ther. 2008, 324, 475-483
17. Pacher, P.; Batkai, S.; Kunos, G. The endocannabinoid system as an emerging target of pharmacotherapy Pharmacol. Rev. 2006, 58, 389-462
18. Compton, D. R.; Rice, K. C.; De Costa, B. R.; Razdan, R. K.; Melvin, L. S.; Johnson, M. R.; Martin, B. R. Cannabinoid structure-activity relationships: correlation of receptor binding and in vivo activities J. Pharmacol. Exp. Ther. 1993, 265, 218-226
19. Huffman, J. W. Cannabimimetic indoles, pyrroles and indenes Curr. Med. Chem. 1999, 6, 705-720
20. Palmer, S. L.; Thakur, G. A.; Makriyannis, A. Cannabinergic ligands Chem. Phys. Lipids 2002, 121, 3-19
21. Raitio, K. H.; Salo, O. M.; Nevalainen, T.; Poso, A.; Jarvinen, T. Targeting the cannabinoid CB2 receptor: mutations, modeling and development of CB2 selective ligands Curr. Med. Chem. 2005, 12, 1217-1237
22. Marriott, K. S.; Huffman, J. W. Recent advances in the development of selective ligands for the cannabinoid CB(2) receptor Curr. Top. Med. Chem. 2008, 8, 187-204
23. Yang, P.; Wang, L.; Xie, X. Q. Latest advances in novel cannabinoid CB(2) ligands for drug abuse and their therapeutic potential Future Med. Chem. 2012, 4, 187-204
24. Rinaldi-Carmona, M.; Barth, F.; Millan, J.; Derocq, J. M.; Casellas, P.; Congy, C.; Oustric, D.; Sarran, M.; Bouaboula, M.; Calandra, B.; Portier, M.; Shire, D.; Breliere, J. C.; Le Fur, G. L. SR 144528, the first potent and selective antagonist of the CB2 cannabinoid receptor J. Pharmacol. Exp. Ther. 1998, 284, 644-650
25. Ross, R. A.; Brockie, H. C.; Stevenson, L. A.; Murphy, V. L.; Templeton, F.; Makriyannis, A.; Pertwee, R. G. Agonist-inverse agonist characterization at CB1 and CB2 cannabinoid receptors of L759633, L759656, and AM630 Br. J. Pharmacol. 1999, 126, 665-672
26. Iwamura, H.; Suzuki, H.; Ueda, Y.; Kaya, T.; Inaba, T. In vitro and in vivo pharmacological characterization of JTE-907, a novel selective ligand for cannabinoid CB2 receptor J. Pharmacol. Exp. Ther. 2001, 296, 420-425
27. Lunn, C. A.; Fine, J. S.; Rojas-Triana, A.; Jackson, J. V.; Fan, X.; Kung, T. T.; Gonsiorek, W.; Schwarz, M. A.; Lavey, B.; Kozlowski, J. A.; Narula, S. K.; Lundell, D. J.; Hipkin, R. W.; Bober, L. A. A novel cannabinoid peripheral cannabinoid receptor-selective inverse agonist blocks leukocyte recruitment in vivo J. Pharmacol. Exp. Ther. 2006, 316, 780-788
28. Schuehly, W.; Paredes, J. M.; Kleyer, J.; Huefner, A.; Anavi-Goffer, S.; Raduner, S.; Altmann, K. H.; Gertsch, J. Mechanisms of osteoclastogenesis inhibition by a novel class of biphenyl-type cannabinoid CB(2) receptor inverse agonists Chem. Biol. 2011, 18, 1053-1064
29. 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, 2597-2600
30. Xi, Z.-X.; Peng, X.-Q.; Li, X.; Song, R.; Zhang, H.-Y.; Liu, Q.-R.; Yang, H.-J.; Bi, G.-H.; Li, J.; Gardner, E. L. Brain cannabinoid CB2 receptors modulate cocaine's actions in mice Nat. Neurosci. 2011, 14, 1160-1166
31. Gertsch, J.; Leonti, M.; Raduner, S.; Racz, I.; Chen, J. Z.; Xie, X. Q.; Altmann, K. H.; Karsak, M.; Zimmer, A. Beta-caryophyllene is a dietary cannabinoid Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 9099-9104
32. Zhong, H.; Bowen, J. P. GALAHAD pharmacophore modeling for drug discovery J. Am. Chem. Soc. 2007, 129, 5780-5780
33. SYBYL 8.0; Tripos: St. Louis, MO, U.S., 2007.
34. Xie, X. Q.; Chen, J. Data-mining a small molecule drug screening representative subset from NIH PubChem database J. Chem. Inf. Model. 2008, 48, 465-475
35. Francisco, M. E.; Seltzman, H. H.; Gilliam, A. F.; Mitchell, R. A.; Rider, S. L.; Pertwee, R. G.; Stevenson, L. A.; Thomas, B. F. Synthesis and structure-activity relationships of amide and hydrazide analogues of the cannabinoid CB(1) receptor antagonist N -(piperidinyl)-5-(4-chlorophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1 H -pyrazole-3-carboxamide (SR141716) J. Med. Chem. 2002, 45, 2708-2719
36. Zhang, Y.; Xie, Z.; Wang, L.; Schreiter, B.; Lazo, J. S.; Gertsch, J.; Xie, X. Q. Mutagenesis and computer modeling studies of a GPCR conserved residue W5.43(194) in ligand recognition and signal transduction for CB2 receptor Int. Immunopharmacol. 2011, 11, 1303-1310
37. Anandarajah, A. P.; Schwarz, E. M.; Totterman, S.; Monu, J.; Feng, C. Y.; Shao, T.; Haas-Smith, S. A.; Ritchlin, C. T. The effect of etanercept on osteoclast precursor frequency and enhancing bone marrow oedema in patients with psoriatic arthritis Ann. Rheum. Dis. 2008, 67, 296-301
38. Myint, K. Z.; Xie, X.-Q. Recent advances in fragment-based QSAR and multi-dimensional QSAR methods Int. J. Mol. Sci. 2010, 11, 3846-3866
39. Chen, J.-Z.; Han, X.-W.; Liu, Q.; Makriyannis, A.; Wang, J.; Xie, X.-Q. 3D-QSAR studies of arylpyrazole antagonists of cannabinoid receptor subtypes CB1 and CB2. A combined NMR and CoMFA approach J. Med. Chem. 2006, 49, 625-636
40. Xie, X. Q.; Melvin, L. S.; Makriyannis, A. The conformational properties of the highly selective cannabinoid receptor ligand CP-55,940 J. Biol. Chem. 1996, 271, 10640-10647
41. Xie, X.-Q.; Chen, J.-Z.; Billings, E. M. 3D structural model of the G-protein-coupled cannabinoid CB2 receptor Proteins: Struct., Funct., Bioinf. 2003, 53, 307-319
42. Diaz, P.; Phatak, S. S.; Xu, J.; Astruc-Diaz, F.; Cavasotto, C. N.; Naguib, M. 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. 2008, 52, 433-444
43. Gouldson, P.; Calandra, B.; Legoux, P.; Kerneis, A.; Rinaldi-Carmona, M.; Barth, F.; Le Fur, G.; Ferrara, P.; Shire, D. Mutational analysis and molecular modeling of the antagonist SR 144528 binding site on the human cannabinoid CB2 receptor Eur. J. Pharmacol. 2000, 401, 17-25
44. Poso, A.; Huffman, J. W. Targeting the cannabinoid CB2 receptor: modelling and structural determinants of CB2 selective ligands Br. J. Pharmacol. 2008, 153, 335-346
45. Wan, J. P.; Chai, Y. F.; Wu, J. M.; Pan, Y. J. N, N ′- (Phenylmethylene)diacetamide analogues as economical and efficient ligands in copper-catalyzed arylation of aromatic nitrogen-containing heterocycles Synlett 2008, 3068-3072
46. Bayer, A.; Maier, M. E. Synthesis of enamides from aldehydes and amides Tetrahedron 2004, 60, 6665-6677
47. Feng, R.; Anderson, G.; Xiao, G.; Elliott, G.; Leoni, L.; Mapara, M. Y.; Roodman, G. D.; Lentzsch, S. SDX-308, a nonsteroidal anti-inflammatory agent, inhibits NF-kappaB activity, resulting in strong inhibition of osteoclast formation/activity and multiple myeloma cell growth Blood 2007, 109, 2130-2138
48. Feng, R.; Ma, H.; Hassig, C. A.; Payne, J. E.; Smith, N. D.; Mapara, M. Y.; Hager, J. H.; Lentzsch, S. KD5170, a novel mercaptoketone-based histone deacetylase inhibitor, exerts antimyeloma effects by DNA damage and mitochondrial signaling Mol. Cancer Ther. 2008, 7, 1494-1505
49. SYBYL X1.2; Tripos (1699 South Hanley Rd, St. Louis, MO, 63144, U.S.); software available at www.tripos.com.