Recent progress in the discovery of niacin receptor agonists

Current Opinion in Drug Discovery and Development

Volumn 10, Issue 4, 2007, Pages 452-459

  Semple, G ^a   Boatman, P D ^a   Richman, J G ^a  

^a ARENA PHARMACEUTICALS   (United States)

Author keywords

Atherosclerosis; Free fatty acids; GPR109a; HDL; HM74a; Niacin

Indexed keywords

4 FLUOROPHENYL ACIFRAN DERIVATIVE; 5 BROMO 3 THIENYL ACIFRAN DERIVATIVE; 5 BUTYLPYRAZOLE 3 CARBOXYLIC ACID; 5 CHLORO 3 THIENYL ACIFRAN DERIVATIVE; ACETYLSALICYLIC ACID; ACIFRAN; ANTHRANILIC ACID DERIVATIVE; ANTILIPEMIC AGENT; BARBITURIC ACID DERIVATIVE; CARBOXYLIC ACID DERIVATIVE; CYTOCHROME P450 2C8; CYTOCHROME P450 2C9; FATTY ACID; G PROTEIN COUPLED RECEPTOR; G PROTEIN COUPLED RECEPTOR 109A; GSK 256073; ISOXAZOLE; LIGAND; LIPID; MITOGEN ACTIVATED PROTEIN KINASE; MK 0354; NICOTINIC ACID; NICOTINIC ACID RECEPTOR AGONIST; PROSTAGLANDIN D2; UNCLASSIFIED DRUG; XANTHINE DERIVATIVE;

DOSE RESPONSE; DRUG EFFECT; DRUG EFFICACY; DRUG POTENCY; DRUG RESEARCH; DRUG STRUCTURE; DRUG TARGETING; FLUSHING; HIGH THROUGHPUT SCREENING; IN VIVO STUDY; LIGAND BINDING; LIPOLYSIS; MUTAGENESIS; NONHUMAN; PATENT; RECEPTOR UPREGULATION; REVIEW; STRUCTURE ACTIVITY RELATION;

ANIMALS; DRUG DESIGN; NIACIN; RECEPTORS, G-PROTEIN-COUPLED;

EID: 34447622295     PISSN: 13676733     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (64)

1. Carlson LA: Niaspan, the prolonged release preparation of nicotinic acid (niacin), the broad-spectrum lipid drug. Int J Clin Pract (2004) 58(7):706-713.
2. Carlson LA: Nicotinic acid: The broad-spectrum lipid drug. A 50th anniversary review. J Intern Med (2005) 258(2):94-114. •• A comprehensive review of the discovery and clinical use of niacin over the last fifty years.
3. Carlson LA, Orö L: Persistence of the inhibitory effect of nicotinic acid on catecholamine-stimulated lipid mobilization during prolonged treatment with nicotinic acid. J Atheroscler Res (1965) 5:436-439.
4. Carlson LA: Inhibition of the mobilization of free fatty acids from adipose tissue. Physiological aspects on the mechanisms for the inhibition of mobilization of FFA from adipose tissue. Ann NY Acad Sci (1965) 131(1):119-142.
5. Carlson LA, Froberg S, Orö L: A case of massive hypertriglyceridemia corrected by nicotinic acid or nicotinamide therapy. Atherosclerosis (1972) 16(3):359-368.
6. No Authors Listed: The Coronary Drug Project: Design, methods, and baseline results. Circulation (1973) 47(3 Suppl):1-179.
7. Canner PL, Berge KG, Wenger NK, Stamler J, Friedman L, Prineas RJ, Friedewald W: Fifteen year mortality in Coronary Drug Project patients: Long-term benefit with niacin. J Am Coll Cardiol (1986) 8(6):1245-1255.
8. Brown BG, Zhao XQ, Chait A, Fisher LD, Cheung MC, Morse JS, Dowdy AA, Marino EK, Bolson EL, Alaupovic P, Frohlich J et al: Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med (2001) 345(22):1583-1592.
9. Taylor AJ, Sullenberger LE, Lee HJ, Lee JK, Grace KA: Arterial biology for the investigation of the treatment effects of reducing cholesterol (ARBITER) 2: A double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins. Circulation (2004) 110(23):3512-3517.
10. Lorenzen A, Stannek C, Lang H, Andrianov V, Kalvinsh I, Schwabe U: Characterization of a G protein-coupled receptor for nicotinic acid. Mol Pharmacol (2001) 59(2):349-357. •• Confirmation that niacin could interact with a G-protein-coupled receptor. This study directs efforts toward the molecular identification of the receptor towards Gi-coupled receptors.
11. Wise A, Foord SM, Fraser NJ, Barnes AA, Elshourbagy N, Eilert M, Ignar DM, Murdock PR, Steplewski K, Green A, Brown AJ et al: Molecular identification of high and low affinity receptors for nicotinic acid. J Biol Chem (2003) 278(11):9869-9874. • The first molecular identification of the human receptors for niacin.
12. Tunaru S, Kero J, Schaub A, Wufka C, Blaukat A, Pfeffer K, Offermanns S: PUMA-G and HM74 are receptors for nicotinic acid and mediate its anti-lipolytic effect. Nat Med (2003) 9(3):352-355.
13. Schaub A, Futterer A, Pfeffer K: PUMA-G, an IFN-γ-inducible gene in macrophages is a novel member of the seven transmembrane spanning receptor superfamily. Eur J Immunol (2001) 31(12):3714-3725.
14. Tunaru S, Lattig J, Kero J, Krause G, Offermanns S: Characterization of determinants of ligand binding to the nicotinic acid receptor GPR109A (HM74A/PUMA-G). Mol Pharmacol (2005) 68(5):1271-1280. •• A comprehensive molecular modeling and mutagenesis study to identify the ligand binding site of niacin and related molecules to GPR109a.
15. Carlson LA, Orö L: The effect of nicotinic acid on the plasma free fatty acid; demonstration of a metabolic type of sympathicolysis. Acta Med Scand (1962) 172:641-645.
16. Carlson LA: Studies on the effect of nicotinic acid on catecholamine stimulated lipolysis in adipose tissue in vitro. Acta Med Scand (1963) 173:719-722.
17. Holland GF, Pereira JN: Heterocyclic tetrazoles, a new class of lipolysis inhibitors. J Med Chem (1967) 10(2):149-154.
18. Rizzi A, Jori A, Veneroni E, Garattini S: Effect of 3,5-dimethylpyrazole on blood free fatty acids and glucose. Life Sci (1964) 3:1371-1375.
19. Dulin WE, Gerritsen GC: Effects of 5-carboxy-3-methylisoxazole on carbohydrate and fat metabolism. Proc Soc Exp Biol Med (1966) 121(3):777-779.
20. Pereira JN, Holland GF: The development of resistance to a potent lipolysis inhibitor, 3-methylisoxazole-5-carboxylic acid. J Pharmacol Exp Ther (1967) 157(2):381-387.
21. Seki K, Isegawa J, Fukuda M, Ohki M: Studies on hypolipidemic agents. II. Synthesis and pharmacological properties of alkylpyrazole derivatives. Chem Pharm Bull (Tokyo) (1984) 32(4): 1568-1577.
22. van Herk T, Brussee J, van den Nieuwendijk AM, van der Klein PA, Ijzerman AP, Stannek C, Burmeister A, Lorenzen A: Pyrazole derivatives as partial agonists for the nicotinic acid receptor. J Med Chem (2003) 46(18):3945-3951. • The first SAR study of pyrazole acids to measure binding and function of compounds on rat spleen and adipocyte membranes.
23. Skinner PJ, Cherrier MC, Webb PJ, Shin Y-J, Gharbaoui T, Tamura SY, Chen R, Richman JG, Semple G: Fluorinated pyrazole acids are agonists of the high affinity niacin receptor GPR109a. 30th National Medicinal Chemistry Symposium, Seattle, WA, USA (2006).
24. Semple G: Discovery of selective agonists for GPR109A and GPR109B, the high and low affinity receptors for niacin. GPCRs in Medicinal Chemistry, Verona, Italy (2006).
25. Jirkovsky I, Cayen MN: Hypolipidemic 4,5-dihydro-4-oxo-5,5- disubstituted-2-furancarboxylic acids. J Med Chem (1982) 25(10): 1154-1156.
26. Mahboubi K, Witman-Jones T, Adamus JE, Letsinger JT, Whitehouse D, Moorman AR, Sawicki D, Bergenhem N, Ross SA: Triglyceride modulation by acifran analogs: Activity towards the niacin high and low affinity G protein-coupled receptors HM74A and HM74. Biochem Biophys Res Commun (2006) 340(2):482-490.
27. Jung JK, Johnson BR, Duong T, Decaire M, Uy J, Gharbaoui T, Boatman PD, Sage CR, Chen R, Richman JG, Connolly DT et al: Analogues of acifran: Agonists of the high and low affinity niacin receptors, GPR109a and GPR109b. J Med Chem (2007) 50(7):1445-1448 • The first study of compounds that interact with GPR109a that uses the activity of compounds with cloned human receptors to drive the SAR studies.
28. Shen HC, Ding F-X, Deng Q, Wilsie L, Krsmanovic M, Taggart A, Wu T-J, Wu K, Jin L, Cheng K, Ciecko T et al: The discovery of biaryl and tricyclic anthranilides as potent agonists for the high affinity niacin receptor GPR109A. Molecular Medicine Tri-conference, San Francisco, CA, USA (2007). • The first SAR study of anthranilides, including perhaps the least niacin-like series yet described. The series highlights the optimization of the inner and terminal ring portions of the lead structure.
29. Aktories K, Jakobs KH: In vivo and in vitro desensitization of nicotinic acid-induced adipocyte adenylate cyclase inhibition. Naunyn Schmiedebergs Arch Pharmacol (1982) 318(3):241-245.
30. Green A, Milligan G, Dobias SB: Gi down-regulation as a mechanism for heterologous desensitization in adipocytes. J Biol Chem (1992) 267(5):3223-3229.
31. Myles DD, Stratton GD, Strong P, Skidmore IF: The development of tolerance to antilipolytic agents in rats. Biochem Pharmacol (1985) 34(2):269-274.
32. Taggart AK, Kero J, Gan X, Cai TQ, Cheng K, Ippolito M, Ren N, Kaplan R, Wu K, Wu TJ, Jin L et al: (D)-β-Hydroxybutyrate inhibits adipocyte lipolysis via the nicotinic acid receptor PUMA-G. J Biol Chem (2005) 280(29):26649-26652. • The identification of a weak endogenous agonist of GPR109a.
33. Vertua R, Usardi MM, Bombelli R, Farkas T, Paoletti R: The effect of nicotinic acid on free fatty acid mobilization. Life Sci (1964) 3:281-286.
34. 2 release following oral administration of niacin in humans. J Invest Dermatol (1992) 98(5):812-815.
35. Benyó Z, Gille A, Kero J, Csiky M, Suchánková MC, Nüsing RM, Moers A, Pfeffer K, Offermanns S: GPR109A (PUMA-G/HM74A) mediates nicotinic acid-induced flushing. J Clin Invest (2005) 115(12):3634-3640. •• A comprehensive study showing that GPR109a (PUMA-G) is required for niacin to induce a flushing effect.
36. 2 receptor 1 suppresses nicotinic acid-induced vasodilation in mice and humans. Proc Natl Acad Sci USA (2006) 103(17):6682-6687.
37. 2 in vivo in humans following the administration of nicotinic acid. Prostaglandins (1989) 38(2):263-274.
38. Benyó Z, Gille A, Bennett CL, Clausen BE, Offermanns S: Nicotinic acid-induced flushing is mediated by activation of epidermal Langerhans cells. Mol Pharmacol (2006) 70(6):1844-1849.
39. 2 in response to nicotinic acid. J Invest Dermatol (2006) 126(12):2637-2646.
40. Turenne SD, Seeman M, Ross BM: An animal model of nicotinicacid- induced vasodilation: Effect of haloperidol, caffeine and nicotine upon nicotinic acid response. Schizophr Res (2001) 50(3):191-197.
41. Richman JG, Kanemitsu-Parks M, Gaidarov I, Cameron JS, Griffin P, Zheng H, Guerra NC, Cham L, Maciejewski-Lenoir D, Behan DP, Boatman D et al: Nicotinic acid receptor agonists differentially activate downstream effectors. J Biol Chem (2007) 282(25):18028-18036.
42. ARENA PHARMACEUTICALS INC (Semple G, Gharbaoui T, Shin Y-J, Decaire M, Averbuj C, Skinner PJ): Preparation of 5-substituted 2H-pyrazole-3-carboxylic acid derivatives as agonists for the RUP25 nicotinic acid receptor for the treatment of dyslipidemia and related diseases. WO-2005011677 (2005).
43. ARENA PHARMACEUTICALS INC/MERCK & CO INC (Semple G, Schrader T, Skinner PJ, Colletti SL, Gharbaoui T, Imbriglio JE, Jung J-K, Liang R, Raghavan, S, Schmidt D Tata JR): Tetrazole derivatives and methods of treatment of metabolic-related disorders thereof. WO-2005044816 (2005).
44. MERCK & CO INC (Imbriglio JE, Colletti SL, Tata JR, Liang R, Raghavan S, Schmidt, DR, Smenton, AR Chan SY): Niacin receptor agonists, compositions containing such compounds and methods of treatment. WO-2006113150 (2006).
45. ARENA PHARMACEUTICALS INC (Boatman DP, Schrader TO, Semple G, Skinner PJ, Jung, J-K): Fused pyrazole derivatives and methods of treatment of metabolic-related disorders thereof. WO-2006069242 (2006).
46. AMERICAN HOME PRODUCTS CORP (Jirkovsky IL, Dvornik D, Cayen MN): Hypolipidemic derivatives of 4,5-dihydro-4-oxo-furan-2-carboxylic acids preparation from alpha hydroxyl-ketone(s) and dialkyl oxalate cpds. US-4169202 (1978).
47. SMITHKLINE BEECHAM CORP (Campbell M, Hatley RJ, Heer JP, Mason, AM, Pinto IL, Rahman SS, Smith IED): Preparation of anthranilic acid derivatives as selective agonists of the nicotinic acid receptor HM74A. WO-2005016867 (2005).
48. SMITHKLINE BEECHAM CORP (Campbell M, Hatley RJ, Heer JP, Mason AM, Nicholson NH, Pinto IL, Rahman SS, Smith IED): Preparation of anthranilic acid derivatives as selective agonists of the nicotinic acid receptor HM74A. WO-2005016870 (2005).
49. SMITHKLINE BEECHAM CORP (Campbell M, Mason AM, Pinto IL, Pollard DR, Smith IED): Anthranilic acid derivatives and their use in treatment of diseases of lipid metabolism, in particular dyslipidaemia. WO-2006085108 (2006).
50. SMITHKLINE BEECHAM CORP (Mason AM, Pinto IL, Rahman SS): Anthranilic acid derivatives active at the HM74A receptor. WO-2006085111 (2006).
51. SMITHKLINE BEECHAM CORP (Hatley R, Mason AM, Pinto IL, Smith IED): Preparation of anthranilic acid derivatives treating diseases active at the HM74A receptor. WO-2006085112 (2006).
52. SMITHKLINE BEECHAM CORP (Pinto IL, Simpson JK): Preparation of heteroaryl carboxylic acid derivatives for treatment of diseases characterized by under activation of HM74A receptor. WO-2006085113 (2006).
53. MERCK & CO INC (Colletti SL, Beresis RT, Chen W, Tata JR, Shen HC, Marley DM, Deng Q, Frie JL, Ding F-X): N-acyl anthranilic acid and related compounds as niacin receptor agonists, and their preparation, pharmaceutical compositions and methods of treatment of dyslipidemias. WO-2006052555 (2006).
54. MERCK & CO INC (Colletti SL, Tata JR, Shen HC, Ding F-X, Frie JL, Imbriglio JE, Chen W): Niacin agonists, compositions containing such compounds and methods of treatment. WO-2006057922 (2006).
55. MERCK & CO INC (Raghavan S, Colletti SL, Ding F-X, Shen H, Tata JR, Lins AR, Smenton AL, Chen W, Schmidt DR, Tria GS): Preparation of 2-acylaminocycloalkenecarboxylic acids derivatives as niacin receptor agonists. US-20060293364 (2006).
56. HOFFMANN LA ROCHE INC (Dehmlow H, Grether U, Kratochwil NA, Narquizian R, Panousis C, Peters J-U): Preparation of benzoylanthranilic acid derivatives as G-protein-coupled receptor HM74A agonists. US-20060281810 (2006).
57. INCYTE CORP (Cao G, Xue C-B, Anand R, Huang T, Kong L, Glenn J, Feng H): Disubstituted thienyl compounds and their use as pharmaceuticals. WO-2007015744 (2007).
58. SMITHKLINE BEECHAM CORP (Pinto IL, Rahman SS, Nicholson NH): Preparation of xanthine derivatives as HM74A agonists. WO-2005077950 (2005).
59. SMITHKLINE BEECHAM CORP (Hatley RJD, Pinto IL): Preparation of xanthine derivatives as HM74A agonists. WO-2006045564 (2006).
60. SMITHKLINE BEECHAM CORP (Hatley RJD Pinto IL): Preparation of halogenoalkyl xanthine derivatives as HM74A agonists. WO-2006045565 (2006).
61. SMITHKLINE BEECHAM CORP (Hatley RJD, Mason AM, Pinto IL): Xanthine derivatives as selective HM74A agonists. WO-2007017261 (2007).
62. SMITHKLINE BEECHAM CORP (Hatley, RJD, Heer JP, Liddle J, Mason AM, Pinto IL, Rahman SS, Smith IED): Xanthine derivatives as selective HM74A agonists. WO-2007017262 (2007).
63. SMITHKLINE BEECHAM CORP (Heer JP, Smith IED): Xanthine derivatives as selective HM74A agonists. WO-2007017265 (2007).
64. SCHERING CORP (Palani A, Su J, Xiao D, Huang X, Rao AU, Chen X, Tang H, Qin J, Huang Y, Aslanian RG, McKittrick B): Pyrano[2,3-d]pyrimidines as nicotinic acid receptor agonists for the treatment of dyslipidemia and their preparation and pharmaceutical compositions. WO-2006124490 (2006).