ACS Medicinal Chemistry Letters
Letter
Treatment effects of Niaspan, a controlled release niacin, in patients
with hypercholesterolemia: A placebo controlled trial. J. Cardiovasc.
Pharmacol. Ther. 1996, 1, 195−202.
(11) Paolini, J. F.; Mitchel, Y. B.; Reyes, R.; Kher, U.; Lai, E.; Watson,
D. J.; Norquist, J. M.; Meehan, A. G.; Bays, H. E.; Davidson, M.;
Ballantyne, C. M. Effects of laropiprant on nicotinic acid induced
flushing in patients with dyslipidemia. Am. J. Cardiol. 2008, 101, 625−
630.
(12) 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, 349−357.
(13) Wise, A.; Foord, S. M.; Fraser, N. J.; Barnes, A. A.; Elshourbagy,
N.; Eilert, M.; Ignar, D. M.; Murdock, P. R.; Steplewski, K.; Green, A.;
Brown, A, J.; Dowell, S. J.; Szekeres, P. G.; Hassall, D. G.; Marshall, F.
H.; Wilson, S.; Pike, N. B. Molecular identification of high and low
affinity receptors for nicotinic acid. J. Biol. Chem. 2003, 278, 9869−
9874.
flow increases (flushing) observed with NA in the dog models
were not observed with compound 33, suggesting that it has an
improved therapeutic window to flushing as compared to NA.
This compound was investigated and developed further for its
clinical potential.32 Data from the phase I and phase II studies
will be the subject of future publications.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures for assay protocols, in vivo studies,
and synthesis and characterization of compounds 1−-36. This
material is available free of charge via the Internet at http://
AUTHOR INFORMATION
Corresponding Author
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(14) 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 antilipolytic effect. Nat. Med. 2003, 9, 352−355.
(15) Torhan, A. S.; Cheewatrakoolpong., B.; Kwee, L.; Greenfeder, S.
Cloning and characterization of the hamster and guinea pig nicotinic
acid receptors. J. Lipid Res. 2007, 48, 2065−2071.
*Tel: 908-740-7158. Fax: 908-740-7664. E-mail: anandan.
Notes
The authors declare no competing financial interest.
(16) Offermanns, S.; Colletti, S. L.; Lovenberg, T. W.; Semple, G.;
Wise, A.; Ijzerman, A. P. International Union of Basic and Clinical
Pharmacology. LXXXII: Nomenclature and classification of Hydroxy
carboxylic Acid Receptors (GPR81, GPR109A, GPR109B). Pharmacol.
Rev. 2011, 63, 269−290.
ACKNOWLEDGMENTS
We thank Drs. John Piwinski, Catherine Strader, Michael Graziano,
and Jean Lachowicz for their strong support.
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(17) Carlson, L. A.; Oro, L. The effect of nicotinic acid on the plasma
̈
ABBREVIATIONS
free fatty acid; demonstration of a metabolic type of sympathicolysis.
Acta Med. Scand. 1962, 172, 641−645.
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NA, nicotinic acid; FFA, free fatty acid; VLDL-C, very low-
density lipoprotein cholesterol; LDL-C, low-density lipoprotein
cholesterol; TG, triglyceride; Lp-a, lipoprotein a; HDL-C, high-
density lipoprotein cholesterol; CAD, coronary artery disease;
NAR, nicotinic acid receptor; GPR, G-protein coupled receptor;
cAMP, 3′-5′-cyclic adenosine monophosphate; PK, pharmacoki-
netic; CYP, cytochrome P450; BUN, blood urea nitrogen; TFA,
trifluoroacetic acid; CDI, 1,1′-carbonyldiimidazole
(18) Carlson, L. A. Studies on the effects of nicotinic acid on
catecholamine stimulated lipolysis in adipose tissue in vitro. Acta Med.
Scand. 1963, 173, 719−722.
3
(19) Carlson, L. A.; Hanngren, A. Initial distribution in mice of H-
labeled nicotinic acid studied with autoradiography. Life Sci. 1964, 3,
867−871.
(20) Butcher, R. W.; Baird, C. E.; Sutherland, E. W. Effects of
lipolytic and antilipolytic substances on adenosine 3′, 5′-
monophosphate levels in isolated fat cells. J. Biol. Chem. 1968, 243,
1705−1712.
(21) Aktories, K.; Schultz, G.; Jakobs, K. H. Regulation of adenylate
cyclase activity in hamster adipocites. Inhibition by prostaglandins,
α-adrenergic agonists and nicotinic acid. Naunyn-Schmiedeberg's Arch.
Pharmacol. 1980, 312, 167−173.
(22) Sprecher, D. L. Raising high-density lipoprotein cholesterol with
niacin and fibrates: A comparative review. Am. J. Cardiol. 2000, 86,
46−50.
(23) Le Goff, W.; Guerin, M.; Chapman, M. J. Pharmacological
modulation of cholesteryl ester transfer protein, a new therapeutic
target in atherogenic dyslipidemia. Pharmacol. Ther. 2004, 101, 17−38.
(24) Semple, G.; Boatman, P. D.; Richman, J. G. Recent progress in
the discovery of niacin receptor agonists. Curr. Opin. Drug Discovery
Dev. 2007, 10, 452−459.
(25) Boatman, P. D.; Richman, J. G.; Semple, G. Nicotinic acid
receptor agonists. J. Med. Chem. 2008, 51, 7653−7662.
(26) Shen, H. C.; Colletti, S. L. Novel patent publications on high-
affinity nicotinic acid receptor agonists. Expert Opin. Ther. Pat. 2009,
19, 957−967.
(27) Shen, H. C.; Colletti, S. L. High-affinity niacin receptor
GPR109A agonists. Annu. Rep. Med. Chem. 2010, 45, 73−94.
(28) Qin, J.; Rao, A.; Chen, X.; Zhu, X.; Liu, Z.; Huang, X.; Degrado,
S.; Huang, Y.; Xiao, D.; Aslanian, R.; Cheewatrakoolpong, B.; Zhang,
H.; Greenfeder, S.; Farley, C.; Cook, J.; Kurowski, S.; Li, Q.; van Heek,
M.; Chintala, M.; Wang, G.; Hsieh, Y.; Li, F.; Palani, A. Discovery of a
potent nicotinic acid receptor agonist for the treatment of
dyslipidemia. ACS Med. Chem. Lett. 2011, 2, 171−176.
REFERENCES
■
(1) Altschul, R.; Hoffer, A.; Stephen, J. D. Influence of nicotinic acid
on serum cholesterol in man. Arch. Biochem. 1955, 54, 558−559.
(2) Carlson, L. A. Nicotinic acid: The broad-spectrum lipid drug. A
50th anniversary review. J. Int. Med. 2005, 258, 94−114.
(3) Gotto, A. M. Jr. Low high-density lipoprotein cholesterol as a risk
factor in coronary heart disease. A working group report. Circulation
2001, 103, 2213−2218.
(4) Offermanns, S. The nicotinic acid receptor GPR109A (HM74A
or PUMA-G) as a new therapeutic agent. Trends Pharmacol. Sci. 2006,
27, 384−390.
(5) Coronary Drug Project. Clofibrate and niacin in coronary heart
disease. J. Am. Med. Assoc. 1975, 231, 360−381.
(6) Canner, P. L.; Berge, K. G.; Wenger, N. K.; Stamler, J.; Friedman,
L.; Prineas, R. J.; Friedewald, W. Fifteen year in Coronary Drug
Project patients: Long-term benefit with niacin. J. Am. Coll. Cardiol.
1986, 8, 1245−1255.
(7) Berge, K. G.; Canner, P. L. Coronary drug project: experience
with niacin. Coronary Drug Project Research Group. Eur. J. Clin.
Pharmacol. 1991, 40 (Suppl. 1), S49−S51.
(8) Goldsmith, G. A.; Cordill, S. The vasodilating effects of nicotinic
acid (relation to metabolic rate and body temperature). Am. J. Med. Sci.
1943, 205, 204−208.
(9) Hiatt, J. G.; Shamsie, S. G.; Schectman, G. Discontinuation rates
of cholesterol-lowering medications: Implications for primary care.
Am. J. Manage. Care 1999, 5, 437−444.
(10) Morgan, J. M.; Capuzzi, D. M.; Guyton, J. R.; Centor, R. M.;
Goldberg, R.; Robbins, D. C.; Dipette, D.; Jenkins, S.; Marcovina, S.
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