Spirocyclic delta opioid receptor agonists for the treatment of pain: Discovery of N,N-diethyl-3-hydroxy-4-(spiro[chromene-2,4′-piperidine]-4- yl) benzamide (ADL5747)

Journal of Medicinal Chemistry

Volumn 52, Issue 18, 2009, Pages 5685-5702

  Bourdonnec, Bertrand Le ^a   Windh, Rolf T ^a   Leister, Lara K ^a   Zhou, Q Jean ^a   Ajello, Christopher W ^a   Gu, Minghua ^a,b   Chu, Guo Hua ^a   Tuthill, Paul A ^a   Barker, William M ^a   Koblish, Michael ^a   Wiant, Daniel D ^a   Graczyk, Thomas M ^a   Belanger, Serge ^a   Cassel, Joel A ^a   Feschenko, Marina S ^a   Brogdon, Bernice L ^a   Smith, Steven A ^a,c   Derelanko, Michael J ^a   Kutz, Steve ^a   Little, Patrick J ^a   Dehaven, Robert N ^a   DeHaven Hudkins, Diane L ^a   Dolle, Roland E ^a   more..

^a ADOLOR CORPORATION   (United States)

^b GLAXOSMITHKLINE   (United States)

^c UCB PHARMA   (Belgium)

Author keywords

[No Author keywords available]

Indexed keywords

4 [ALPHA (4 ALLYL 2,5 DIMETHYL 1 PIPERAZINYL) 3 HYDROXYBENZYL] N,N DIETHYLBENZAMIDE; 4 [ALPHA (4 ALLYL 2,5 DIMETHYL 1 PIPERAZINYL) 3 METHOXYBENZYL] N,N DIETHYLBENZAMIDE; ADL 5747; ADL 5859; ANALGESIC AGENT; BENZAMIDE DERIVATIVE; CHROMENE DERIVATIVE; CYTOCHROME P450 2D6; DELTA OPIATE RECEPTOR; DELTA OPIATE RECEPTOR AGONIST; FREUND ADJUVANT; GUANOSINE 5' O (3 THIOTRIPHOSPHATE); INDOMETACIN; KAPPA OPIATE RECEPTOR; MORPHINE; MU OPIATE RECEPTOR; N,N DIETHYL 3 HYDROXY 4 (SPIRO[CHROMENE 2,4' PIPERIDIN] 4 YL)BENZAMIDE; NALTRINDOLE; PIPERIDINE DERIVATIVE; POTASSIUM CHANNEL HERG; SB 235863; SPIRO COMPOUND; UNCLASSIFIED DRUG;

ANALGESIC ACTIVITY; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL TISSUE; AREA UNDER THE CURVE; ARTICLE; BINDING AFFINITY; CONVULSION; DOG; DOSE RESPONSE; DRUG BIOAVAILABILITY; DRUG BLOOD LEVEL; DRUG BRAIN LEVEL; DRUG CLEARANCE; DRUG DISTRIBUTION; DRUG ELIMINATION; DRUG HALF LIFE; DRUG METABOLISM; DRUG POTENCY; DRUG PROTEIN BINDING; DRUG RECEPTOR BINDING; DRUG SAFETY; DRUG SELECTIVITY; DRUG SYNTHESIS; HUMAN; HUMAN CELL; HYPERALGESIA; IC 50; INFLAMMATION; MALE; NONHUMAN; PAIN; RAT; SINGLE DRUG DOSE; STRUCTURE ACTIVITY RELATION;

ANALGESICS; ANIMALS; BENZAMIDES; BENZOPYRANS; CHO CELLS; CLINICAL TRIALS AS TOPIC; CRICETINAE; CRICETULUS; CRYSTALLOGRAPHY, X-RAY; CYTOCHROME P-450 CYP2D6; DOGS; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG DISCOVERY; ETHER-A-GO-GO POTASSIUM CHANNELS; HUMANS; HYPERALGESIA; MALE; PAIN; RATS; RATS, SPRAGUE-DAWLEY; RECEPTORS, OPIOID, DELTA; SPIRO COMPOUNDS;

EID: 70349433775     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm900773n     Document Type: Article

References (60)

1. Aldrich, J. V. Analgesics. In Burger's Medicinal Chemistry and Drug Discovery; Wolff, M. E., Ed.; John Wiley & Sons: New York, 1996; Vol.3, pp 321-341.
2. 2]deltorphin-I. Synapse 1993, 13, 231-240.
3. Traynor, J. R.; Hunter, J. C.; Rodrigues, R. E.; Hill, R. G.; Hughes, J. Delta-opioid receptor binding sites in rodent spinal cord. Br. J. Pharmacol. 1990, 100, 319-323.
4. Quirion, R.; Zajac, J. M.; Morgat, J. L.; Roques, B. P. Autoradiographic distribution of mu and delta opiate receptors in rat brain using highly selective ligands. Life Sci. 1983, 33, 227-230.
5. 3H]DSLET binding: evidence for distinct delta 1 and delta 2 opioid receptor populations in rat brain. Brain Res. 1996, 719, 85-95.
6. Tempel, A.; Zukin, R. S. Neuroanatomical patterns of the μ, δ, and κ opioid receptors of rat brain as determined by quantitative in vitro autoradiography. Neurobiology 1987, 84, 4308-4312.
7. Pradhan, A. A. A.; Clarke, P. B. S. Comparison between δ-opioid receptor functional response and autoradiographic labeling in rat brain and spinal cord. J. Comp. Neurol. 2005, 481, 416-426.
8. Mansour, A.; Fox, C. A.; Burke, S.; Meng, F.; Thompson, R. C.; Akil, H.; Watson, S. J. Mu, delta, and kappa opioid receptor mRNA expression in the rat CNS: an in situ hybridization study. J. Comp. Neurol. 1994, 350, 412-438.
9. George, S. R.; Zastawny, R. L.; Briones-Urbina, R.; Cheng, R.; Nguyen, T.; Heiber, M.; Kouvelas, A.; Chan, A. S.; O'Dowd, B. F. Distinct distributions of mu, delta and kappa opioid receptor mRNA in rat brain. Biochem. Biophys. Res. Commun. 1994, 205, 1438-1444.
10. Bausch, S. B.; Patterson, T. A.; Appleyard, S. M.; Chavkin, C. Immunocytochemical localization of delta opioid receptors in mouse brain. J. Chem. Neuroanat. 1995, 8, 175-189.
11. Cahill, C. M.; McClellan, K. A.; Morinville, A.; Hoffert, C.; Hubatsch, D.; O'Donnell, D.; Beaudet, A. Immunohistochemical distribution of delta opioid receptors in the rat central nervous system: evidence for somatodendritic labeling and antigen-specific cellular compartmentalization. J. Comp. Neurol. 2001, 440, 65-84.
12. Fraser, G. L.; Gaudreau, G.-A.; Clarke, P. B. S.; Menard, D. P.; Perkins, M. N. Antihyperalgesic effects of δ opioid agonists in a rat model of chronic inflammation. Br. J. Pharmacol. 2000, 129, 1668-1672.
13. Brandt, M. R.; Furness, M. S.; Mello, N. K.; Rice, K. C.; Negus, S. S. Antinociceptive effects of δ-opioid agonists in rhesus monkeys: effects on chemically induced thermal hypersensitivity. J. Pharmacol. Exp. Ther. 2001, 296, 939-946.
14. Petrillo, P.; Angelici, O.; Bingham, S.; Ficalora, G.; Garnier, M.; Zaratin, P. F.; Petrone, G.; Pozzi, O.; Sbacchi, M.; Stean, T. O.; Upton, N.; Dondio, G. M.; Scheideler, M. A. Evidence for a selective role in the δ-opioid agonist [8R-(4βS*,8aα,8aβ,12bβ)]7,10- dimethyl-1-methoxy-11-(2-methylpropyl)oxycarbonyl 5,6,7,8,12,12β-hexahydro- (9H)-4,8-methanobenzofuro[3,2-e]pyrrolo[2,3-g]isoquinoline hydrochloride (SB-235863) in blocking hyperalgesia associated with inflammatory and neuropathic pain responses. J. Pharmacol. Exp. Ther. 2003, 307, 1079-1089.
15. Desmeules, J. A.; Kayser, V.; Guilbaud, G. Selective opioid receptor agonists modulate mechanical allodynia in an animal model of neuropathic pain. Pain 1993, 53, 277-285. (Pubitemid 23172376)
16. Mika, J.; Przewlocki, R.; Przewlocka, B. The role of delta-opioid receptor subtypes in neuropathic pain. Eur. J. Pharmacol. 2001, 415, 31-37.
17. Craft, R. M.; Henley, S. R.; Haaseth, R. C.; Hruby, V. J.; Porreca, F. Opioid antinociception in a rat model of visceral pain: systemic versus local drug administration. J. Pharmacol. Exp. Ther. 1995, 275, 1535-1542.
18. 5] enkephalin or intravenous U50,488H on the visceromotor response to colorectal distension in the rat. Anesthesiology 1995, 83, 336-343.
19. Danzebrink, R. M.; Green, S. A.; Gebhart, G. F. Spinal mu and delta, but not kappa, opioid-receptor agonists attenuate responses to noxious colorectal distension in the rat. Pain 1995, 63, 39-47.
20. Broom, D. C.; Jutkiewicz, E. M.; Rice, K. C.; Traynor, J. R.; Woods, J. H. Behavioral effects of δ-opioid receptor agonists: potential antidepressants? Jpn. J. Pharmacol. 2002, 90, 1-6.
21. Jutkiewicz, E. M. The antidepressant-like effects of delta-opioid receptor agonists. Mol. Interventions 2006, 6, 162-169. (Pubitemid 43998814)
22. Gross, G. J. Role of opioids in acute and delayed preconditioning. J. Mol. Cell. Cardiol. 2003, 35, 709-718.
23. Henry, B.; Fox, S. H.; Crossman, A. R.; Brotchie, J. M. Mu- and delta-opioid receptor antagonists reduce levodopa-induced dyskinesia in the MPTP-lesioned primate model of Parkinson's disease. Exp. Neurol. 2001, 171, 139-146.
24. Hill, M. P.; Hille, C. J.; Brotchie, J. M. Delta-opioid receptor agonists as a therapeutic approach in Parkinson's disease. Drug News Perspect. 2000, 13, 261-268. (Pubitemid 30728229)
25. Szeto, H. H.; Soong, Y.; Wu, D.; Olariu, N.; Kett, A.; Kim, H.; Clapp, J. F. Respiratory depression after intravenous administration of delta-selective opioid peptide analogs. Peptides 1999, 20, 101-105.
26. Negus, S. S.; Gatch, M. B.; Mello, N. K.; Zhang, X.; Rice, K. Behavioral effects of the delta-selective opioid agonist SNC80 and related compounds in rhesus monkeys. J. Pharmacol. Exp. Ther. 1998, 286, 362-375.
27. Sheldon, R. J.; Riviere, J. M.; Malarchik, M. E.; Mosberg, I.; Burks, T. F.; Porreca, F. Opioid regulation of mucosal ion transport in the mouse isolated jejunum. J. Pharmacol. Exp. Ther. 1990, 253, 144-151.
28. Cowan, A.; Zhu, X. Z.; Mosberg, H. I.; Omnaas, J. R.; Porreca, F. Direct dependence studies in rats with agents selective for different types of opioid receptor. J. Pharmacol. Exp. Ther. 1988, 246, 950-955.
29. Lee, P. H.; McNutt, R. W.; Chang, K. J. A nonpeptidic delta opioid receptor agonist, BW373U86, attenuates the development and expression of morphine abstinence precipitated by naloxone in rat. J. Pharmacol. Exp. Ther. 1993, 267, 883-887.
30. Brandt, M. R.; Furness, M. S.; Rice, K. C.; Fischer, B. D.; Negus, S. S. Studies of tolerance and dependence with the δ-opioid agonist SNC80 in rhesus monkeys responding under a schedule of food presentation. J. Pharmacol. Exp. Ther. 2001, 299, 629-637.
31. Negus, S. S.; Butelman, R.; Chang, K.-J.; DeCosta, B.; Winger, G.; Woods, J. H. Behavioral effects of the systemically active delta opioid agonist BW373U86 in rhesus monkeys. J. Pharmacol. Exp. Ther. 1994, 270, 1025-1034.
32. Chang, K. J.; Rigdon, G. C.; Howard, J. L.; McNutt, R. W. A novel, potent and selective nonpeptidic delta opioid receptor agonist BW373U86. J. Pharmacol. Exp. Ther. 1993, 267, 852-857.
33. Calderon, S. N.; Coop, A. SNC-80 and related δ opioid agonists. Curr. Pharm. Des. 2004, 10, 733-742.
34. Wei, Z.-Y.; Brown, W.; Takasaki, B.; Plobeck, N.; Delorme, D.; Zhou, F.; Yang, H.; Jones, P.; Gawell, L.; Gagnon, H.; Schmidt, R.; Yue, S.-Y.; Walpole, C.; Payza, K.; St-Onge, S.; Labarre, M.; Godbout, C.; Jakob, A.; Butterworth, J.; Kamassah, A.; Morin, P.-E.; Projean, D.; Ducharme, J.; Roberts, E. N,N-Diethyl-4-(phenylpiperidin-4-ylidenemethyl)benzamide: a novel, exceptionally selective, potent δ opioid receptor agonist with oral bioavailability and its analogues. J. Med. Chem. 2000, 43, 3895-3905.
35. Plobeck, N.; Delorme, D.; Wei, Z.-Y.; Yang, H.; Zhou, F.; Schwarz, P.; Gawell, L.; Gagnon, H.; Pelcman, B.; Schmidt, R.; Yue, S.-Y.; Walpole, C.; Brown, W.; Zhou, E.; Labarre, M.; Payza, K.; St-Onge, S.; Kamassah, A.; Morin, P.-E.; Projean, D.; Ducharme, J.; Roberts, E. New diarylmethylpiperazines as potent and selective nonpeptidic δ opioid receptor agonists with increased in vitro metabolic stability. J. Med. Chem. 2000, 43, 3878-3894.
36. Calderon, S. N.; Rothman, R. B.; Porreca, F.; Flippen-Anderson, J. L.; McNutt, R. W.; Xu, H.; Smith, L. E.; Bilsky, E. J.; Davis, P.; Rice, K. C. Probes for narcotic receptor mediated phenomena. 19. Synthesis of (+)-4-[(αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl) -3-methoxybenzyl]-N,N-diethylbenzamide (SNC 80): a highly selective, nonpeptide delta opioid receptor agonist. J. Med. Chem. 1994, 37, 2125-2128.
37. Calderon, S. N.; Rice, K. C.; Rothman, R. B.; Porreca, F.; Flippen-Anderson, J. L.; Kayakiri, H.; Xu, H.; Becketts, K.; Smith, L. E.; Bilsky, E. J.; Davis, P.; Horvath, R. Probes for narcotic receptor mediated phenomena. 23. Synthesis, opioid receptor binding, and bioassay of the highly selective delta agonist (+)-4-[(rR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1- piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC 80) and related novel nonpeptide delta opioid receptor ligands. J. Med. Chem. 1997, 40, 695-704.
38. Comer, S. D.; Hoenicke, E. M.; Sable, A. I.; McNutt, R. W.; Chang, K. J.; De Costa, B. R.; Mosberg, H. I.; Woods, J. H. Convulsive effects of systemic administration of the delta opioid agonist BW373U86 in mice. J. Pharmacol. Exp. Ther. 1993, 267, 888-895.
39. Broom, D. C.; Nitsche, J. F.; Pintar, J. E.; Rice, K. C.; Woods, J. H.; Traynor, J. R. Comparison of receptor mechanisms and efficacy requirements for δ-agonist-induced convulsive activity and antinociception in mice. J. Pharmacol. Exp. Ther. 2002, 303, 723-729.
40. Broom, D. C.; Jutkiewicz, E. M.; Folk, J. E.; Traynor, J. R.; Rice, K. C.; Woods, J. H. Convulsant activity of a non-peptidic delta-opioid receptor agonist is not required for its antidepressant-like effects in Sprague-Dawley rats. Psychopharmacology 2002, 164, 42-48.
41. Dykstra, L. A.; Schoenbaum, G. M.; Yarbrough, J.; McNutt, R.; Chang, K.-J. A novel delta opioid agonist, BW373U86, in squirrel monkeys responding under a schedule of shock titration. J. Pharmacol. Exp. Ther. 1993, 267, 875-882.
42. Pakarinen, E. D.; Woods, J. H.; Moerschbaecher, J. M. Repeated acquisition of behavioral chains in squirrel monkeys: comparisons of a mu, kappa and delta opioid agonist. J. Pharmacol. Exp. Ther. 1995, 272, 552-559.
43. Tortella, F. C.; Echevarria, E.; Robles, L.; Mosberg, H. I.; Holaday, J. W. Anticonvulsant effects of mu (DAGO) and delta (DPDPE) enkephalins in rats. Peptides 1998, 9, 1177-1181.
44. 2-COOH)-Bid (UFP-512), a novel selective delta opioid receptor agonist. Peptides 2008, 29, 93-103.
45. Tortella, F. C.; Robles, L.; Mosbeg, H. L.; Holaday, J. W. Electroencephalographic assessment of the role of δ receptors in opioid peptide-induced seizures. Neuropeptides 1984, 5, 213-216.
46. Le Bourdonnec, B.; Windh, R. T.; Ajello, C. W.; Leister, L. K.; Gu, M.; Chu, G.-H.; Tuthill, P. A.; Barker, W. M.; Koblish, M.; Wiant, D. D.; Graczyk, T. M.; Belanger, S.; Cassel, J. A.; Feschenko, M. S.; Brogdon, B. L.; Smith, S. A.; Christ, D. D.; Derelanko, M. J.; Kutz, S.; Little, P. J.; DeHaven, R. N.; DeHaven-Hudkins, D. L.; Dolle, R. E. Potent, orally bioavailable delta opioid receptor agonists for the treatment of pain: Discovery of N,N-diethyl-4-(5- hydroxyspiro[chromene-2,40-piperidine]-4-yl)benzamide (ADL5859). J. Med. Chem. 2008, 51, 5893-5896.
47. Crystallographic data for compound 50 has been deposited with the Cambridge Crystallographic Data Centre as supplementary publication No.CCDC 719968. Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, (fax:+44 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk).
48. + channel. A model for bad behavior. J. Med. Chem. 2003, 46, 2017-2022.
49. Ioannides, C. Cytochromes P450: Role in the Metabolism and Toxicity of Drugs and Other Xenobiotics; Royal Society of Chemistry: Cambridge, UK, 2008.
50. Spina, E.; Scordo, M. G. Clinically significant drug interactions with antidepressants in the elderly. Drugs Aging 2002, 19, 299-320. (Pubitemid 34686722)
51. Hemeryck, A.; Belpaire, F. M. Selective serotonin reuptake inhibitors and cytochrome P-450 mediated drug-drug interactions: an update. Curr. Drug Metab. 2002, 3, 13-37.
52. Sproule, B. A.; Naranjo, C. A.; Bremner, K. E.; Hassan, P. C. Selective serotonin reuptake inhibitors and CNS drug interactions. A critical review of the evidence. Clin. Pharmacokinet. 1997, 33, 454-471.
53. DeHaven-Hudkins, D. L.; Burgos, L. C.; Cassel, J. A.; Daubert, J. D.; DeHaven, R. N.; Mansson, E.; Nagasaka, H.; Yu, G.; Yaksh, T. Loperamide (ADL 2-1294), an opioid antihyperalgesic agent with peripheral selectivity. J. Pharmacol. Exp. Ther. 1999, 289, 494-502.
54. All housing conditions and experimental procedures were performed in accordance with the "Guide for the Care and Use of Laboratory Animals". Experimental procedures followed the ethical guidelines of the IASP and were approved by the Adolor Corporation Institutional Animal Care and Use Committee.
55. Davies, B.; Morris, T. Physiological parameters in laboratory animals and humans. Pharm. Res. 1993, 10, 1093-1095.
56. 2: a dynorphin analogue with high selectivity for the κ opioid receptor. J. Med. Chem. 2000, 43, 2698-2702.
57. Bradford, M. M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem. 1976, 72, 248-254.
58. Selley, D. E.; Sim, L. J.; Xiao, R.; Liu, Q.; Childers, S. R. μ-Opioid receptor-stimulated guanosine-5′-O-(γthio)-triphosphate binding in rat thalamus and cultured cell lines: signal transduction mechanisms underlying agonist efficacy. Mol. Pharmacol. 1997, 51, 87-96.
59. Traynor, J. R.; Nahorski, S. R. Modulation by μ-opioid agonists of guanosine-5′O-(3-[35S]thio)triphosphate binding to membranes from human neuroblastoma SH-SY5Y Cells. Mol. Pharmacol. 1995, 47, 848-854.
60. Chauret, N.; Dobbs, B.; Lackman, R. L.; Bateman, K.; Nicoll-Griffith, D. A.; Stresser, D. M.; Ackermann, J. M.; Turner, S. D.; Miller, V. P.; Crespi, C. L. The use of 3-[2-(N,N-diethyl-N-methylammonium)ethyl]-7-methoxy-4- methylcoumarin (AMMC) as a specific CYP2D6 probe in human liver microsomes. Drug Metab. Dispos. 2001, 29, 1196-1200.