MC4 receptor antagonists: A potential treatment for cachexia

IDrugs

Volumn 8, Issue 4, 2005, Pages 314-319

  Foster, Alan C ^a   Chen, Chen ^a   Markison, Stacy ^a   Marks, Daniel L ^b,c  

^a NEUROCRINE BIOSCIENCES INC   (United States)

^b OREGON HEALTH AND SCIENCE UNIVERSITY   (United States)

^c OREGON HEALTH AND SCIENCE UNIVERSITY   (United States)

Author keywords

Body weight regulation; Cachexia; MC4 receptor; Melanocortins

Indexed keywords

2 [2 [2 (5 BROMO 2 METHOXYPHENYL)ETHYL] 3 FLUOROPHENYL] 4,5 DIHYDRO 1H IMIDAZOLE; AUTORECEPTOR; BENZAMIDINE; BENZYLAMINE DERIVATIVE; CYTOKINE; HORMONE RECEPTOR BLOCKING AGENT; HORMONE RECEPTOR STIMULATING AGENT; IMIDAZOLE DERIVATIVE; INTERLEUKIN 1BETA; MB 243; MBP 10; MCL 0129; MELANOCORTIN 1 RECEPTOR; MELANOCORTIN 2 RECEPTOR; MELANOCORTIN 3 RECEPTOR; MELANOCORTIN 4 RECEPTOR; MELANOCORTIN 5 RECEPTOR; N ACETYL ALPHA INTERMEDIN[4-10]CYCLO[4 NORLEUCINE 5 ASPARTIC ACID 7 [3 (2 NAPHTHYL)ALANINE] 10 LYSINAMIDE]; NBI 12I; NBI 30; PROOPIOMELANOCORTIN; RECEPTOR BLOCKING AGENT; TETRAHYDROISOQUINOLONE; TUMOR NECROSIS FACTOR ALPHA; UNCLASSIFIED DRUG;

ANOREXIA; ANTIINFLAMMATORY ACTIVITY; BINDING AFFINITY; BODY WEIGHT DISORDER; CACHEXIA; DRUG BIOAVAILABILITY; DRUG DESIGN; DRUG EFFICACY; DRUG INDUSTRY; DRUG MECHANISM; DRUG POTENCY; DRUG RECEPTOR BINDING; DRUG STRUCTURE; DRUG SYNTHESIS; EXPERIMENTAL MODEL; GENE DELETION; GENETIC ANALYSIS; LEAN BODY WEIGHT; NONHUMAN; OBESITY; REVIEW; STRUCTURE ANALYSIS;

ANIMALS; CACHEXIA; HUMANS; NAPHTHALENES; PIPERAZINES; RECEPTOR, MELANOCORTIN, TYPE 4;

EID: 19944421460     PISSN: 13697056     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (46)

1. Tisdale MJ: Biology of cachexia. J Natl Cancer Inst (1997) 89(23):1763-1773.
2. Larkin M: Thwarting the dwindling progression of cachexia. Lancet (1998) 351(9112):1336.
3. Bruera E: ABC of palliative rare. Anorexia, cachexia, and nutrition. Br Med J (1997) 315(7117):1219-1222.
4. Inui A: Cancer anoroxia-cachexia syndrome: Current Issues in research and management. CA Cancer J Clin (2002) 52(2):72-91.
5. Loprinzi CL, Scheid DJ, Dose AM, Burnham NL, Jensen MD: Body-composition changes in patients who gain weight while receiving megestrol acetate. J Clin Oncol (1993) 11(1):152-154.
6. Cone RD (Ed): The Melanocortin System. Ann NY Acad Sci (2003) 994:1-383.
7. Cone RD, Cowley MA, Bulter AA, Fan W, Marks DL, Low MJ: The arcuate nucleus as a conduit for diverse signals relevant to energy homeostasis. Int J Obesity Relat Metab Disord (2001) 25(Suppl 5):S63-S67.
8. Huszar D, Lynch CA, Fairchild-Huntress V, Dunmore JH, Fang Q, Berkemeier LR, Gu W, Kesterson RA, Boston BA, Cone RD, Smith FJ et al: Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell (1997) 88(1):131-141.
9. O'Rahilly S, Yeo GS, Farooqi IS: Melanocortin receptors weigh in. Nat Med (2004) 10(4):351-352.
10. Krude H, Biebermann H, Luck W, Horn R, Brabant G, Gruters A: Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat Genet (1998) 19(2):155-157.
11. Fan W, Boston BA, Kesterson RA, Hruby VJ, Cone RD: Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature (1997) 385(6612):165-168.
12. Cepoi D, Phillips T, Cismowski M, Goodfellow VS, Ling N, Cone RD, Fan W: Assessment of a small molecule melanocortin-4 receptor-specific agonist on energy homeostasis. Brain Res (2004) 1000(1-2):64-71.
13. Palucki BL, Park MK, Nargund RP, Ye Z, Sebhat IK, Pollard PG, Kalyani RN, Tang R, MacNeil T, Weinberg DH, Vongs A et al: Discovery of (2S)-N-[(1R)-2-[4-cyclohexyl-4-[[(1,1-dimethylethyl)- amino]carbonyl]-1-piperidinyl]-1-[(4-fluorophenyl)methyl]-2-oxoethyl] -4-methyl-2-piperazinecarboxamide (MB243), a potent and selective melanocortin subtype-4 receptor agonist. Bioorg Med Chem Lett (2004) 15(1):171-175.
14. Lu XY, Nicholson JR, Akil H, Watson SJ: Time course of short-term and long-term orexigenic effects of agouti-related protein (86-132). Neuroreport (2001) 12(6):1281-1284.
15. Joppa MA, Ling N, Chen C, Gogas KR, Foster AC, Markison S: Central administration of peptide and small molecule MC4 receptor antagonists induce hyerphagia in mice and attenuate cytokine-induced anorexia. Peptides (2005): in press.
16. Marks DL, Ling N, Cone RD: Role of the central melanocortin system in cachexia. Cancer Res (2001) 61(4):1432-1438.
17. Wisse BE, Frayo RS, Schwartz MW, Cummings DE: Reversal of cancer anorexia by blockade of central melanocortin receptors in rats. Endocrinology (2001) 142(8):3292-3301.
18. Marks DL, Butler AA, Turner R, Brookhart G, Cone RD: Differential role of molanocortin receptor subtypes in cachexia. Endocrinology (2003) 144(4):1513-1523.
19. Kalantar-Zadeh K, Kopple JD: Relative contributions of nutrition and inflammation to clinical outcome in dialysis patients. Am J Kidney Dis (2001) 38(6):1343-1350.
20. Mehrotra R, Kopple JD: Nutritional management of maintenance dialysis patients: Why aren't we doing better? Annu Rev Nutr (2001) 21:343-379.
21. Mak RH, Cheung W, Cone RD, Marks, DL: The impact of leptin and cytokine signaling on nutrition in chronic kidney disease. Pediatr Nephrol (2005): in press.
22. Lawrence CB, Rothwell NJ: Anorexic but not pyrogenic actions of interleukin-1 are modulated by central malanocortin-3/4 receptors in the rat. J Neuroendocrinol (2001) 13(6):490-495.
23. Getting SJ, Allcock GH, Flower R, Perretti M: Natural and synthetic agonists of melanocortin receptor type 3 possess anti-inflammatory properties. J Leukocyte Biol (2001) 69(1):98-104.
24. Cowley MA, Smart JL, Rubinstein M, Carden MG, Diano S, Horvath TL, Cone RD, Low MJ: Lepdn activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature (2001) 411(6836):480-484.
25. Plata-Salaman CR: Immunomodulators, and feeding regulation: A humoral link between the immune and nervous systems. Brain Behav Immun (1989) 3(3):193-213.
26. Inui A: Cancer anorexia-cachexia syndrome: Are neuropeptides the key? Cancer Res (1999) 59(18):4493-4501.
27. Scarlett JM, Joppa MJ, Markison S, Foster AC, Brookhart G, Marks DL: Direct activation of the hypothalamic melanocortin system by interleukin-1. Abs Endocr Soc (2004):OR6-3.
28. Sebhat IK, Martin WJ, Ye Z, Barakat K, Mosley RT, Johnston DB, Bakshi R, Palucki B, Weinberg DH, MacNeil T, Kalyani RN et al: Design and pharmacology of N-[(3R)-1,2,3,4- tetrahydroisoquinolinium-3-ylcarbonyl]-(1R)-1-(4-chlorobenzyl)-2-[4- cyclohexyl-4-(1H-1,2,4-triazol-1-ylmethyl)piperidin-1-yl]-2- oxoethylamine (1), a potent, selective, melanocortin subtype-4 receptor agonist. J Med Chem (2002) 45(21):4589-4593.
29. Pan K, Scott MK, Lee DH, Fitzpatrick LJ, Crooke JJ, Rivero RA, Rosenthal DI, Vaidya AH, Zhao B, Reitz AB: 2,3-Diaryl-5-anilino[1,2,4]thiadiazoles as melanocortin MC4 receptor agonists and their effects on feeding behavior in rats. Bioorg Med Chem (2003) 11(2):185-192.
30. Herpin TF, Yu G, Carlson KE, Morton GC, Wu X, Kang L, Tuerdi H, Khanna A, Tokarski JS, Lawrence RM, Macor JE: Discovery of tyrosine-based potent and selective melanocortin-1 receptor small molecule agonists with anti-inflammatory properties. J Med Chem (2003) 46(7):1123-1126.
31. 2. Bioorg Med Chem Lett (2003) 13(14):2337-2340.
32. Dyck B, Parker J, Philips T, Carter L, Murphy B, Summers R, Hermann J, Baker T, Cismowski M, Saunders J, Goodfellow V: Aryl piperazine melanocortin MC4 receptor agonists. Bioorg Med Chem Lett (2003) 13(21):3793-3796.
33. Ruel R, Herpin TF, Iben L, Luo G, Martel A, Mason H, Mattson G, Poirier B, Ruediger EH, Shi D, Thibault C et al: β-Alanine dipeptides as MC4R agonists. Bioorg Med Chem Lett (2003) 13(24):4341-4344.
34. Ujjainwalla F, Warner D, Walsh TF, Wyvratt MJ, Zhou C, Yang L, Kalyani RN, MacNeil T, Van der Ploeg LH, Rosenblum CI, Tang R et al: Design and synthesis of melanocortin subtype-4 receptor agonists: Evolution of the pyridazinone archetype. Bioorg Med Chem Lett (2003) 13(24):4431-4435.
35. Richardson TI, Ornstein PL, Briner K, Fisher MJ, Backer RT, Biggers CK, Clay MP, Emmerson PJ, Hertel LW, Hsiung HM, Husain S et al: Synthesis and structure-activity relationships of novel arylpiperazines as potent and selective agonists of the melanocortin subtype-4 receptor. J Med Chem (2004) 47(3):744-755.
36. Xi N, Hale C, Kelly MG, Norman MH, Stec M, Xu S, Baumgartner JW, Fotsch C: Synthesis of novel melanocortin 4 receptor agonists and antagonists containing a succinamide core. Bioorg Med Chem Lett (2004) 14(2):377-381.
37. Mutulis F, Yahorava S, Mutule I, Yahorau A, Liepinsh E, Kopantshuk S, Veiksina S, Tars K, Belyakov S, Mishnev A, Rinken A et al: New substituted piperazines as ligands for the melanocortin receptors. Correlation to the X-ray structure of 'THIQ'. J Med Chem (2004) 47(18):4613-4626.
38. Arasasingham PN, Fotsch C, Ouyang X, Norman MH, Kelly MG, Stark KL, Karbon B, Hale C, Baumgartner JW, Zambrano M, Cheetham J et al: Structure-activity relationship of (1-aryl-2-piperazinyl-ethyl)piperazines: Antagonists for the Agrp/melanocortin receptor binding. J Med Chem (2003) 46(1):9-11.
39. Chaki S, Hirota S, Funakoshi T, Suzuki Y, Suetake S, Okubo T, Ishii T, Nakazato A, Okuyama S: Anxiolytic-like and antidepressant-like activities of MCL0129 (1-[(S)-2-(4-fluorophenyl)-2-(-4-isopropyl-piperadin-1-yl)ethyl]-4-[4-(2 -methoxynaphthalen-1-yl)butyl]piperazine), a novel and potent nonpeptide antagonist of the melanocortin-4 receptor. J Pharmacol Exp Ther (2003) 304(2):818-826.
40. Vos TJ, Caracoti A, Che J, Dai M, Farrer CA, Forsyth NE, Drabic SV, Horlick RA, Lamppu D, Yowe DL, Balani S et al: Identification of 2-[2-[2-(5-bromo-2-methoxyphenyl)-ethyl]-3- fluorophenyl]-4,5-dihydro-1H-imidazole (ML00253764), a small molecule melanocortin 4 receptor antagonist that effectively reduces tumor-induced weight loss in a mouse model. J Med Chem (2004) 47(7):1602-1604.
41. Marsilje TH, Roses JB, Calderwood EF, Stroud SG, Forsyth NE, Blackburn C, Yowe DL, Miao W, Drabic SV, Bohane MD, Scott Daniels J et al: Synthesis and biological evaluation of imidazole-based small molecule antagonists of the melanocortin 4 receptor (MC4-R). Bioorg Med Chem Lett (2004) 14(14):3721-3725.
42. Pontillo J, Tran JA, Arellano M, Fleck BA, Huntley R, Marinkovic D, Lanier M, Nelson J, Parker J, Saunders J, Tucci FC et al: Structure-activity relationships of piperazinebenzylamines as potent and selective agonists of the human melanocortin-4 receptor. Bioorg Med Chem Lett (2004) 14(17):4417-4423.
43. Pontillo J, Tran JA, Fleck BA, Marinkovic D, Arellano M, Tucci FC, Lanier M, Nelson J, Parker J, Saunders J, Murphy B et al: Piperazinebenzylamines as potent and selective antagonists of the human melanocortin-4 receptor. Bioorg Med Chem Lett (2004) 14(22):5605-5609.
44. Chen C, Pontillo, J, Fleck BA, Gao, Y, Wen J-Y, Tran JA, Tucci FC, Marinkovic D, Foster AC, Saunders J: 4-{(2R)-[3-Aminopropionylamido]-3-(2,4-dichlorophenyl)propionyl}-1 -{2-[(2-thienyl)ethylaminomethyl]phenyl}piperazine as a potent and selective melanocortin-4 receptor antagonist - design, synthesis and characterization. J Med Chem (2004) 47(27):6821-6830.
45. Markison S, Foster AC, Chen C, Brookhart GB, Hesse A, Hoare SR, Fleck BA, Brown BT, Marks DL: The regulation of feeding and metabolic rate and the prevention of murine cancer cachexia with a small-molecule melanocortin-4 receptor antagonist. Endocrinology (2005): manuscript submitted.
46. Tucci FC, White NS, Tran JA, Fleck BA, Madan A, Dyck BP, Parker J, Pontillo J, Arellano M, Marinkovic D, Jiang W et al: Potent and orally bioavailable non-peptide antagonists of the human melanocortin-4 receptor based on a series of trans-2-disubstituted cyclohexylpiperazines. J Med Chem (2005): manuscript submitted.