Discovery of 1-[9-(4-chlorophenyl)-8-(2-chlorophenyl)-9H-purin-6-yl]-4- ethylamino-piperidine-4-carboxylic Acid Amide Hydrochloride (CP-945,598), a novel, potent, and selective cannabinoid type 1 receptor antagonist

Journal of Medicinal Chemistry

Volumn 52, Issue 2, 2009, Pages 234-237

  Griffith, David A ^a   Hadcock, John R ^a   Black, Shawn C ^a,b   Iredale, Philip A ^a   Carpino, Philip A ^a   Dasilva Jardine, Paul ^a   Day, Robert ^a,c   Dibrino, Joseph ^a   Dow, Robert L ^a   Landis, Margaret S ^a   O'Connor, Rebecca E ^a   Scott, Dennis O ^a  

^a PFIZER INC   (United States)

^b JOHNSON AND JOHNSON PHARMACEUTICAL RESEARCH AND DEVELOPMENT   (United States)

^c NOVARTIS INSTITUTES FOR BIOMEDICAL RESEARCH   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CANNABINOID 1 RECEPTOR; CANNABINOID 1 RECEPTOR ANTAGONIST; CP 945598; GUANOSINE 5' O (3 THIOTRIPHOSPHATE); POTASSIUM CHANNEL HERG; SULFUR 35; 1 (9 (4 CHLOROPHENYL) 8 (2 CHLOROPHENYL) 9H PURIN 6 YL) 4 ETHYLAMINOPIPERIDINE 4 CARBOXYLIC ACID AMIDE; 1-(9-(4-CHLOROPHENYL)-8-(2-CHLOROPHENYL)-9H-PURIN-6-YL)-4-ETHYLAMINOPIPERIDINE-4-CARBOXYLIC ACID AMIDE; FAT; PIPERIDINE DERIVATIVE; PURINE DERIVATIVE;

ANALGESIA; ANIMAL CELL; ANIMAL EXPERIMENT; ARTICLE; BINDING AFFINITY; CENTRAL NERVOUS SYSTEM; DRUG BLOOD LEVEL; DRUG BRAIN LEVEL; DRUG PENETRATION; DRUG POTENCY; DRUG RECEPTOR BINDING; DRUG RESEARCH; DRUG SELECTIVITY; DRUG SOLUBILITY; DRUG STRUCTURE; DRUG SYNTHESIS; ENERGY EXPENDITURE; FOOD INTAKE; HUMAN; HUMAN CELL; HYPOTHERMIA; LIPID OXIDATION; NONHUMAN; RAT; STRUCTURE ACTIVITY RELATION; WEIGHT REDUCTION; ANIMAL; CHEMISTRY; DOG; DRUG ANTAGONISM; DRUG DEVELOPMENT; ENERGY METABOLISM; METABOLISM; OXIDATION REDUCTION REACTION;

ANIMALS; DOGS; DRUG DISCOVERY; ENERGY METABOLISM; FATS; OXIDATION-REDUCTION; PIPERIDINES; PURINES; RECEPTOR, CANNABINOID, CB1; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 60549088559     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm8012932     Document Type: Article

References (41)

1. Kershaw, E. E.; Flier, J. S. Adipose tissue as an endocrine organ. J. Clin. Endocrinol. Metab. 2004, 89, 2548-2556.
2. Kirkham, T. C. Endocannabinoids in the regulation of appetite and body weight. Behav. Pharmacol. 2005, 16, 297-313.
3. Pagotto, U.; Marsicano, G.; Cota, D.; Lutz, B.; Pasquali, R. The emerging role of the endocannabinoid system in endocrine regulation and energy balance. Endocr. Rev. 2006, 27, 73-100.
4. Matias, I.; Gonthier, M. P.; Orlando, P.; Martiadis, V.; De Petrocellis, L.; Cervino, C.; Petrosino, S.; Hoareau, L.; Festy, F.; Pasquali, R.; Roche, R.; Maj, M.; Pagotto, U.; Monteleone, P.; Di Marzo, V. Regulation, function, and dysregulation of endocannabinoids in models of adipose and beta-pancreatic cells and in obesity and hyperglycemia. J. Clin. Endocrinol. Metab. 2006, 91, 3171-3180.
5. Hao, S.; Avraham, Y.; Mechoulam, R.; Berry, E. M. Low dose anandamide affects food intake, cognitive function, neurotransmitter and corticosterone levels in diet-restricted mice. Eur. J. Pharmacol. 2000, 392, 147-156.
6. Engeli, S.; Böhnke, J.; Feldpausch, M.; Gorzelniak, K.; Janke, J.; Batkai, S.; Pacher, P.; Harvey-White, J.; Luft, F. C.; Sharma, A. M.; Jordan, J. Activation of the peripheral endocannabinoid system in human obesity. Diabetes 2005, 54, 2838-2843.
7. Kirkham, T. C.; Williams, C. M.; Fezza, F.; Di Marzo, V. Endocan-nabinoid levels in rat limbic forebrain and hypothalamus in relation to fasting, feeding and satiation: stimulation of eating by 2-arachi-donoyl glycerol. Br. J. Pharmacol. 2002, 136, 550-557.
8. Jbilo, O.; Ravinet-Trillou, C.; Arnone, M.; Buisson, I.; Bribes, E.; Peleraux, A.; Penarier, G.; Soubrie, P.; Le Fur, G.; Galiegue, S.; Casellas, P. The CB1 receptor antagonist rimonabant reverses the diet- induced obesity phenotype through the regulation of lipolysis and energy balance. FASEB J. 2005, 19, 1567-1569.
9. 1 receptor inverse agonist, rimonabant, modifies body weight and adiponectin function in diet-induced obese rats as a consequence of reduced food intake. Pharmacol., Biochem. Behav. 2006, 84, 353-359.
10. 1 receptor antagonist, SR 141716, on food intake and body weight gain of obese (fa/fa) compared to lean Zucker rats. Psychopharmacology (Berlin) 2003, 167, 103-111.
11. Hildebrandt, A. L.; Kelly-Sullivan, D. M.; Black, S. C. Antiobesity effects of chronic cannabinoid CB1 receptor antagonist treatment in diet-induced obese mice. Eur. J. Pharmacol. 2003, 462, 125-132.
12. Rinaldi-Carmona, M.; Barth, F.; Héaulme, M.; Shire, D.; Calandra, B.; Congy, C.; Martinez, S.; Maruani, J.; Neliat, G.; Caput, D.; et al. SR141716A, a potent and selective antagonist of the brain cannabinoid receptor. FEBS Lett. 1994, 350, 240-244.
13. Lin, L. S.; Lanza, T. J., Jr.; Jewell, J. P.; Liu, P.; Shah, S. K.; Qi, H.; Tong, X.; Wang, J.; Xu, S. S.; Fong, T. M.; Shen, C. P.; Lao, J.; Xiao, J. C.; Shearman, L. P.; Stribling, D. S.; Rosko, K.; Strack, A.; Marsh, D. J.; Feng, Y.; Kumar, S.; Samuel, K.; Yin, W.; Van der Ploeg, L. H.; Goulet, M. T.; Hagmann, W. K. Discovery of N-[(1S,2S)-3-(4-chlorophenyl)-2-(3-cyanophenyl)-1- methylpropyl]-2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide (MK-0364), a novel, acyclic cannabinoid-1 receptor inverse agonist for the treatment of obesity. J. Med. Chem. 2006, 49, 7584-7587.
14. A number of conformationally restricted analogues of SR141716A have been described and recently reviewed: (a) Stoit, A. R.; Lange, J. H.; Hartog, A. P.; Ronken, E.; Tipker, K.; Stuivenberg, H. H.; Dijksman, J. A.; Wals, H. C.; Kruse, C. G. Design, synthesis and biological activity of rigid cannabinoid CB1 receptor antagonists. Chem. Pharm. Bull. (Tokyo) 2002, 50, 1109-1113.
15. (b) Carpino, P. A.; Griffith, D. A.; Sakya, S.; Dow, R. L.; Black, S. C.; Hadcock, J. R.; Iredale, P. A.; Scott, D. O.; Fichtner, M. W.; Rose, C. R.; Day, R.; Dibrino, J.; Butler, M.; Debartolo, D. B.; Dutcher, D.; Gautreau, D.; Lizano, J. S.; O'Connor, R. E.; Sands, M. A.; Kelly-Sullivan, D.; Ward, K. M. New bicyclic cannabinoid receptor-1 (CB1-R) antagonists. Bioorg. Med. Chem. Lett. 2006, 16, 731-736.
16. (c) Thomas, B. F.; Zhang, Y.; Brackeen, M.; Page, K. M.; Mascarella, S. W.; Seltzman, H. H. Conformational characteristics of the interaction of SR141716A with the CB1 cannabinoid receptor as determined through the use of conformationally constrained analogs. AAPS J. 2006, 8, E665-E671.
17. 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.
18. Gleeson, M. P. Generation of a set of simple, interpretable ADMET rules of thumb. J. Med. Chem. 2008, 51, 817-834.
19. Uetrecht, J. N-Oxidation of drugs associated with idiosyncratic drug reactions. Drug Metab. Rev. 2002, 34, 651-665.
20. Timbrell, J. A. The role of metabolism in the hepatotoxicity of isoniazid and iproniazid. Drug Metab. Rev. 1979, 10, 125-147.
21. Zolla, L.; Timperio, A. M. Involvement of active oxygen species in protein and oligonucleotide degradation induced by nitrofurans. Biochem. Cell Biol. 2005, 83, 166-175.
22. We are unaware of reported issues with rimonabant attributed to the hydrazine functionality.
23. 1 receptor. Mol. Pharmacol. 2002, 62, 1274-1287.
24. Minimized using Maestro 8.5. See Supporting Information.
25. Chorvat, R. J.; Bakthavatchalam, R.; Beck, J. P.; Gilligan, P. J.; Wilde, R. G.; Cocuzza, A. J.; Hobbs, F. W.; Cheeseman, R. S.; Curry, M.; Rescinito, J. P.; Krenitsky, P.; Chidester, D.; Yarem, J. A.; Klaczk-iewicz, J. D.; Hodge, C. N.; Aldrich, P. E.; Wasserman, Z. R.; Fernandez, C. H.; Zaczek, R.; Fitzgerald, L. W.; Huang, S. M.; Shen, H. L.; Wong, Y. N.; Chien, B. M.; Arvanitis, A.; et al. Synthesis, corticotropin-releasing factor receptor binding affinity, and pharma-cokinetic properties of triazolo-, imidazo-, and pyrrolopyrimidines and-pyridines. J. Med. Chem. 1999, 42, 833-848.
26. Miyashita, A.; Suzuki, Y.; Iwamoto, K.; Higashino, T. Catalytic action of azolium salts. IX. Synthesis of 6-aroyl-9H-purines and their analogues by nucleophilic aroylation catalyzed by imidazolium or benzimidazolium salt. Chem. Pharm. Bull. 1998, 46, 390-399.
27. Griffith, D. A. Purine Compounds and Uses Thereof. U.S. Patent 7 129 239 B2, 2006.
28. 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, 2490-2497.
29. van de Waterbeemd, H.; Smith, D. A.; Jones, B. C. Lipophilicity in PK design: methyl, ethyl, futile. J. Comput.-Aided Mol. Des. 2001, 15, 273-286.
30. Jamieson, C.; Moir, E. M.; Rankovic, Z.; Wishart, G. Medicinal chemistry of hERG optimizations: highlights and hang-ups. J. Med. Chem. 2006, 49, 5029-5046.
31. Hadcock, J. R.; Griffith, D. A.; Scott, D. O.; Carpino, P. A.; DaSilva- Jardine, P.; Day, R.; Dibrino, J.; Dow, R. L.; Dutcher, D.; Fichtner, M. W.; Gautreau, D.; Hargrove, D.; Iredale, P. A.; Lizano, J. S.; O'Connor, R. E.; Rose, C. R.; Sakya, S.; Sands, M. A.; Swick, A. G.; Tess, D.; Ward, K. M.; Black, S. C. Pharmacological profile of CP-945,598, a potent and selective cannabinoid CB1 receptor antagonist. Clin. Pharmacol. Ther. 2008, 83, S78.
32. Hadcock, J. R.; Griffith, D. A.; Scott, D. O.; Carpino, P. A.; Dow, R. L.; Hargrove, D.; Iredale, P. A.; Kelly-Sullivan, D.; Martin, K. A.; Nardone, N. A.; Swick, A. G.; Black, S. C. The potent and selective cannabinoid CB1 receptor antagonist CP-945,598 exhibits dose-dependent anorectic activity and increased energy expenditure in rats. Clin. Pharmacol. Ther. 2008, 83, S78.
33. 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 Pglycoprotein 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.
34. Scott, D. O.; Hadcock, J. R.; Black, S. C. Comparison of Pre-Clinical Pharmacokinetic and Pharmacodynamic Relationships of Cannabinoid CB1 Receptor Antagonists in a Drug Development Program for Weight Loss Management. Presented at Experimental Biology, San Diego, CA, April 5-9, 2008; No. 711.711 (on CD-ROM).
35. Smith, B. J.; Doran, A. C.; McLean, S.; Tingley, F. D., 3rd; O'Neill, B. T.; Kajiji, S. M. P-glycoprotein efflux at the blood-brain barrier mediates differences in brain disposition and pharmacodynamics between two structurally related neurokinin-1 receptor antagonists. J. Pharmacol. Exp. Ther. 2001, 298, 1252-1259.
36. Boulton, D. W.; DeVane, C. L.; Liston, H. L.; Markowitz, J. S. In vitro P-glycoprotein affinity for atypical and conventional antipsychotics. Life Sci. 2002, 71, 163-169.
37. Holló, Z.; Homolya, L.; Davis, C. W.; Sarkadi, B. Calcein accumulation as a fluorometric functional assay of the multidrug transporter. Biochim. Biophys. Acta 1994, 1191, 384-388.
38. Feng, M. R. Assessment of blood-brain barrier penetration: in silico, in vitro and in vivo. Curr. Drug Metab. 2002, 3, 647-657.
39. Summerfield, S. G.; Stevens, A. J.; Cutler, L.; del Carmen Osuna, M.; Hammond, B.; Tang, S. P.; Hersey, A.; Spalding, D. J.; Jeffrey, P. Improving the in vitro prediction of in vivo central nervous system penetration: integrating permeability, P-glycoprotein efflux, and free fractions in blood and brain. J. Pharmacol. Exp. Ther. 2006, 316, 1282-1290.
40. Hopkins, A. L.; Groom, C. R.; Alex, A. Ligand efficiency: a useful metric for lead selection. Drug Discovery Today 2004, 9, 430-431.
41. Leeson, P. D.; Springthorpe, B. The influence of drug-like concepts on decision-making in medicinal chemistry. Nat. Rev. Drug Discovery 2007, 6, 881-890.