Acyl hydroxypyrazoles as novel agonists for high-affinity nicotinic acid receptor GPR109A: WO2008051403

Expert Opinion on Therapeutic Patents

Volumn 19, Issue 8, 2009, Pages 1149-1155

  Shen, Hong C ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

GPR109A agonists; HM74A; Niacin; Nicotinic acid; Nicotinic acid receptor

Indexed keywords

CHOLESTEROL; FATTY ACID; G PROTEIN COUPLED RECEPTOR; G PROTEIN COUPLED RECEPTOR 109A STIMULATING AGENT; GLUCOSE; HIGH DENSITY LIPOPROTEIN CHOLESTEROL; HORMONE RECEPTOR STIMULATING AGENT; LOW DENSITY LIPOPROTEIN CHOLESTEROL; NICOTINIC AGENT; PYRAZOLE DERIVATIVE; TRIACYLGLYCEROL; UNCLASSIFIED DRUG; WO 2008051403;

AGONIST; ATHEROSCLEROSIS; CHOLESTEROL BLOOD LEVEL; DIABETES MELLITUS; DRUG ACTIVITY; DRUG DESIGN; DRUG RECEPTOR BINDING; DRUG STRUCTURE; DYSLIPIDEMIA; FATTY ACID BLOOD LEVEL; GLUCOSE BLOOD LEVEL; HUMAN; HYDROGEN BOND; IN VITRO STUDY; LIPOPROTEIN BLOOD LEVEL; METABOLIC SYNDROME X; NONHUMAN; PATENT; RECEPTOR AFFINITY; REVIEW; STRUCTURE ACTIVITY RELATION; TRIACYLGLYCEROL BLOOD LEVEL; VASODILATATION;

FATTY ACIDS, NONESTERIFIED; HUMANS; PATENTS AS TOPIC; PYRAZOLES; RECEPTORS, G-PROTEIN-COUPLED; RECEPTORS, NICOTINIC; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 68249100190     PISSN: 13543776     EISSN: None     Source Type: Journal    
DOI: 10.1517/13543770902798061     Document Type: Review

References (32)

1. Mack WJ, Selzer RH, Hodis HN, et al. One-year reduction and longitudinal analysis of carotid intima-media thickness associated with colestipol/niacin therapy. Stroke 1993;24:1779-1783
2. Nikkila EA, Viikinkoski P, Valle M, Frick MH. Prevention of progression of coronary atherosclerosis by treatment of hyperlipidaemia: a seven year prospective angiographic study. Br Med J 1984;289:220-223 (Pubitemid 14014339)
3. Pritzker LB. Do lipid lowering drugs reduce the risk of coronary heart disease? Crit Rev Clin Lab Sci 1998;35:603-621
4. Carlson LA. Nicotinic acid: the broad-spectrum lipid drug. A 50th anniversary review. J Intern Med 2005;258:94-114
5. Knopp RH. Drug treatment of lipid disorders. N Engl J Med 1999;341:498-511
6. Offermanns S. The nicotinic acid receptor GPR109A (HM74A or PUMA-G) as a new therapeutic target. Trends Pharmacol Sci 2006;27:384-390 • An excellent review on GPR109A-related biology. (Pubitemid 43963187)
7. Abbott. Press release. Available from: http://www.abbott.com
8. Paolini JF, Mitchel YB, Reyes R, et al. Effects of laropiprant on nicotinic acid-induced flushing in patients with dyslipidemia. Am J Cardiol 2008;101:625-630
9. SmithKline Beecham Corp. WO9856820; 1998
10. Glaxo Group, Ltd. WO02084298; 2002
11. Wise A, Foord SM, Fraser NJ, et al. Molecular identification of high and low affinity receptors for nicotinic acid. J Biol Chem 2003;278:9869-9874 (Pubitemid 36800490)
12. Tunaru S, Kero J, Schaub A, et al. PUMA-G and HM74 are receptors for nicotinic acid and mediate its anti-lipolytic effect. Nat Med 2003;9:352-355 (Pubitemid 36362793)
13. Arena. US20030166148; 2003
14. Shen HC, Ding F, Taggart A, et al. Discovery of biaryl anthranilides as full agonists for the high affinity niacin receptor. J Med Chem 2007;50:6303-6306 (Pubitemid 350250417)
15. Shen HC, Szymonifka M, Deng Q, et al. Discovery of orally bioavailable and novel urea agonists for the high affinity niacin receptor GPR109A. Bioorg Med Chem Lett 2007;17:6723-6728 (Pubitemid 350061324)
16. Semple G, Skinner PJ, Gharbaoui T, et al. 3-(1H-Tetrazol-5-yl)-1,4,5,6- tetrahydro-cycopentapyrazole (MK-0354): a partial agonist of the nicotinic acid receptor, G-protein coupled receptor 109a, with antilipolytic but no vasodilatory activity in mice. J Med Chem 2008;51:5101-5108 • A paper on the medicinal chemistry leading to a clinical candidate.
17. Lai E, Waters MG, Tata JR, et al. Effect of a niacin receptor partial agonist, MK-0354, on plasma free fatty acids, lipids, and cutaneous flushing in humans. J Clin Lipidol 2008;2:375-383 • Detailed clinical trial protocol and results of a novel NA agonist.
18. Incyte corporation presentation at JP Morgan Healthcare Conference (January 8, 2008;). Available from: http://findarticles.com/p/articles/mi-m0EIN/ is-2008-jan-8/ai-n24224669
19. Study ID NCT00698789. Available from: www.clinicaltrials.gov
20. Semple G, Boatman PD, Richman JG. Recent progress in the discovery of niacin receptor agonists. Curr Opin Drug Discov Dev 2007;10:452-459 (Pubitemid 47093129)
21. Boatman PD, Richman JG, Semple G. Nicotinic acid receptor agonists. J Med Chem 2008;51:7653-7662
22. SmithKline Beecham Corp. WO2005016867; 2005
23. SmithKline Beecham Corp. WO2005016870; 2005
24. SmithKline Beecham Corp. WO2006085113; 2006
25. Merck & Co., Inc. WO2006052555; 2006
26. Merck & Co., Inc. WO2006057922; 2006
27. Merck & Co., Inc. WO2007120575; 2007
28. Merck & Co., Inc. WO2007002557; 2007
29. Merck & Co., Inc. WO2007092364; 2007
30. Tunaru S, Lättig J, Kero J, et al. Characterization of determinants of ligand binding to the nicotinic acid receptor (HM74A/PUMA-G). Mol Pharmacol 2005;68:1271-1280 • The first modeling study on the binding of agonists in GPR109A. (Pubitemid 41539983)
31. Deng Q, Frie JL, Marley DM, et al. Molecular modeling aided design of nicotinic acid receptor GPR109A agonists. Bioorg Med Chem Lett 2008;18:4963-4967 • Modeling studies on anthranilide agonists in the binding pocket of GPR109A.
32. Raghavan S, Tria GS, Shen HC, et al. Tetrahydro anthranilic acid as a surrogate for anthranilic acid: application to the discovery of potent niacin receptor agonists. Bioorg Med Chem Lett 2008;18:3163-3167 (Pubitemid 351718343)