Discovery of a potent nicotinic acid receptor agonist for the treatment of dyslipidemia

Article abstract of DOI:10.1021/ml100251u

Nicotinic acid has been used clinically for decades to control serum lipoproteins. Nicotinic acid lowers very low-density lipoprotein (VLDL)-cholesterol, low-density lipoprotein (LDL)-cholesterol, and lipoprotein-a (LPa), and it is also effective in raising high-density lipoprotein (HDL)-cholesterol. However, nicotinic acid has several side effects in clinical use. The most notable is intense cutaneous vasodilation "flushing"+ on the upper body and face. We discovered a pyranopyrimidinedione series to be nicotinic acid receptor agonists. A potent nicotinic acid receptor agonist from this series {5-(3-cyclopropylpropyl)-2-(difluoromethyl)-3H-pyrano[2,3-d] pyrimidine-4,7-dione}with reduced flushing side effect in dogs was identified.

Full text of DOI:10.1021/ml100251u

pubs.acs.org/acsmedchemlett
Discovery of a Potent Nicotinic Acid Receptor Agonist for
the Treatment of Dyslipidemia
Jun Qin,*,† Ashwin Rao,† Xiao Chen,† Xiaohong Zhu,† Zhidan Liu,† Xianhai Huang,†
Sylvia Degrado,† Ying Huang,† Dong Xiao,† Robert Aslanian,†
Boonlert Cheewatrakoolpong,‡ Hongtao Zhang,‡ Scott Greenfeder,‡
Constance Farley,‡ John Cook,‡ Stan Kurowski,‡ Qiu Li,‡ Margaret van Heek,‡
Madhu Chintala,‡ Ganfeng Wang,§ Yunsheng Hsieh,§ Fangbiao Li,§ and Anandan Palani†
†Department of Medicinal Chemistry, ‡Department of Biology, and §Department of Drug Metabolism & Pharmacokinetics,
Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States
ABSTRACT Nicotinic acid has been used clinically for decades to control serum
lipoproteins. Nicotinic acid lowers very low-density lipoprotein (VLDL)-cholester-
ol, low-density lipoprotein (LDL)-cholesterol, and lipoprotein-a (LPa), and it is also
effective in raising high-density lipoprotein (HDL)-cholesterol. However, nicotinic
acid has several side effects in clinical use. The most notable is intense cutaneous
vasodilation “flushing” on the upper body and face. We discovered a pyranopyr-
imidinedione series to be nicotinic acid receptor agonists. A potent nicotinic acid
receptor agonist from this series {5-(3-cyclopropylpropyl)-2-(difluoromethyl)-3H-
pyrano[2,3-d]pyrimidine-4,7-dione}with reduced flushing side effect in dogs was
identified.
KEYWORDS Nicotinic acid, agonist, flushing, dyslipidemia, VLDL, HDL
chimpanzee, was also identified.20-23 GPR109b is a low
icotinic acid (NA) has been used as a drug to lower
very low-density lipoprotein (VLDL)-cholesterol, low-
density lipoprotein (LDL)-cholesterol, and lipoprotein-a
affinity receptor for nicotinic acid. It has been hypothesized
that activation of GPR109a by nicotinic acid decreases
intracellular cAMP levels in adipocytes. As a downstream
effect, protein kinase A activity is reduced, leading to a
decrease in hormone sensitive lipase activity, eventually
causing the reduction of intracellular triglyceride (TG) hydro-
lysis and free fatty acid (FFA) secretion. This decrease of FFA
production from adipocytes results in a substrate shortage
for liver synthesis and secretion of TG and VLDL, which
eventually leads to a decrease of VLDL, LDL, and TG levels in
plasma.24-28 However, the mechanism of the nicotinic acid-
induced increase of HDL levels in plasma is not known.29,30
Our goal was to identify a compound with better potency
and pharmacokinetic profile than nicotinic acid but no
flushing side effect. Our structure-activity studies started
from the hit compound 1 (Table 1), a thiobarbituric acid
derivative which was obtained from a high-throughput
screen. It showed moderate in vitro potency as a GPR109a
agonist. In order to improve the in vitro activity of 1, we
decided to explore the SAR of the C-2 region first while
maintaining the ethyl group as the C-5 substituent. A variety
of analogues with different C-2 substituents (R1) were pre-
pared (Table 1). The type of substitution clearly influenced
N
(LPa), and it is also effective in raising high-density lipopro-
tein (HDL)-cholesterol in plasma.1-7 Studies have demon-
strated that nicotinic acid is able to reduce the rate of
nonfatal myocardial infarction (MI) and decrease total mor-
tality of patients with a previous history of heart disease.8,9 In
combination with statins, nicotinic acid provided better
therapeutic benefit than taking statins alone.10,11 Despite
all of these encouraging clinical benefits, nicotinic acid is
known to have side effects that limit its clinical use. The most
notable is a severe cutaneous flushing sensation on the
upper body and face.12,13 Other issues include gastrointest-
inal (GI) side effects14 and hepatotoxicity.15-17 Additionally,
patients need to take large quantities of the drug (grams per
day) due to its short half-life, which also leads to compliance
issues. To alleviate this associated flushing side effect, an
extended release formulation of nicotinic acid (NIASPAN) is
available by prescription.18 More recently, a combination of
extended release nicotinic acid and an antagonist of the
prostaglandin D2 receptor (DP) (Tredaptive) has been intro-
duced in Europe. Studies have shown that patients taking
this combination of drugs experienced reduced flushing
symptoms in comparison with taking nicotinic acid alone.19
Nicotinic acid binds with high affinity to a G-protein-
coupled receptor, GPR109a, expressed in human adipose
tissue. A highly related G-protein-coupled receptor, GPR109b,
that shares 95% identity and is only expressed in human and
Received Date: October 18, 2010
Accepted Date: December 2, 2010
Published on Web Date: December 08, 2010
r
2010 American Chemical Society
171
DOI: 10.1021/ml100251u ACS Med. Chem. Lett. 2011, 2, 171–176
|

pubs.acs.org/acsmedchemlett
Table 1. Potency of Compounds in the hu-GPR109a cAMP Assay
a Data represent an average of multiple determinations (n g 3) ( standard deviation.
the activity. When the thiol group of 1 was changed to a
hydrogen atom (2), alkyl (3-5), cyclopropyl (6), alkenyl (7),
aromatic (8), ester (9), nitrile (10), cycloaminoalkyl (11), or
phenylsulfonylalkyl group (12), the activity was lost. In the
case of 13, when R1 was a hydroxymethyl group, moderate
activity was obtained. However, ether analogues 14 and 15
were 3-fold less potent. On the other hand, the fluoroalkyl
group at R1 displayed an interesting profile. Compound 16
with a trifluoromethyl group showed moderate activity
similar to that of 13. Less fluorinated analogues 17 and 18
were much more potent and exhibited slightly better activity
than hit compound 1. Changing R1 from difluoromethyl (17)
to fluorochloromethyl (19) was detrimental to the activity.
Fluoroalkyl derivatives became less tolerated with increas-
ing steric hindrance (20 and 21). Due to the potential to
produce toxic R-fluoroacetic acid from 18, the difluoro-
methyl group of 17 was chosen to be the optimal R1
substituent for carrying out additional SAR on the C-5 region.
Having identified the difluoromethyl group as the optimal
C-2 substituent, we undertook the SAR of the C-5 region. A
series of analogues with different alkyl substituents as R2
were prepared (Table 2). The activity was very sensitive to
subtle changes in the R2 substituent. Although methyl and
propyl analogues, 22 and 23, were much less potent than the
ethyl derivative 17, compounds 24-27 with longer side
chains than propyl retained activity similar to that of 17,
r
2010 American Chemical Society
172
DOI: 10.1021/ml100251u ACS Med. Chem. Lett. 2011, 2, 171–176
|

pubs.acs.org/acsmedchemlett
Table 2. Potency of Compounds in the hu-GPR109a cAMPAssay
cyclopropyl ring maintained excellent activity (41; EC50 =
49 nM). However, the substitution that is tolerated on the
cyclopropyl ring is very limited, as demonstrated in the cases
of 42-47. Steric hindrance played an important role. SAR
studies of this cyclopropyl series eventually led to the
discovery of compounds 39 and 41 with potent in vitro
activity. Compounds tested active, as GPR109a agonists
are full agonists and showed much weaker binding affinity
for the GPR109b (data not shown). The presence of the NH is
important for GPR109a activity, and the acidic NH bond
mimics the role of nicotinic acid.
The synthesis of compounds is exemplified by that of 39 in
Scheme 1. Condensation of malonamide 48 with ethyl
difluoroacetate under basic conditions afforded 49, which
was then cyclized with β-ketoester 51 in acetic acid to
provide 39. β-Ketoester 51 was prepared from acid precursor
50 in one step. The rest of the analogues were synthesized by
methods similar to that of 39.
Although compounds 39 and 41 showed almost identical
in vitro potency (Table 4), they behaved very differently in
vivo. These two compounds were dosed orally in a rat assay
designed to measure reductions in FFA and TG. While 39
demonstrated robust efficacy in vivo (rat FFA -77%, TG -49%,
1 h post 1 mg/kg po dosing), analogue 41 was much less
active (rat FFA -14%, TG -23%, 1 h post 1 mg/kg po
dosing). A detailed examination of their pharmacokinetics
revealed that 39 had much better plasma exposure than 41
a Data represent an average of multiple determinations (n g 3) (
standard deviation.
(39 rat AUC0-6h = 34.1 μg/mL h, 41 AUC0-6h = 3.0 μg/
3
with the pentyl derivative 25 being the best. Introduction of a
large cyclohexyl or cyclopentyl group (28 and 29) was not
tolerated. However, compounds with smaller cyclobutyl or
cyclopropyl substituents (30 and 31) showed good activity.
Given the promising data of compound 30, we further
explored the SAR on this interesting entity. Several cyclobu-
tyl derivatives with different linker lengths (32-34) and ring
substituents (35-36) were prepared (Table 3). The cyclobu-
tylethyl group of 30 retained the best in vitro activity.
Increasing or decreasing linker length in the case of 32-34
had a negative effect on activity. Meanwhile, a methyl
substituent on the cyclobutyl ring (35) was 3-fold less potent
than 30. However, the spirocyclobutyl analogue 36 main-
tained similar activity to that of 30. With the above SAR
results we note that potency is very sensitive to subtle
changes and difficult to predict.
Because of the unpredictable nature of the SAR of the C-5
region, we decided to conduct more detailed SAR on com-
pound 31. This could potentially provide the opportunity to
identify compounds with better activity than the cyclobutyl
series. We synthesized a series of cyclopropyl derivatives
with different linker lengths and substituents on the cyclo-
propyl ring. The data in Table 3 again confirms the unpre-
dictable nature of the SAR. When the substituent was
changed from the cyclopropylethyl of 31 to cyclopropyl (37)
or cyclopropylmethyl (38), the activity was lost. Fortunately,
the cyclopropylpropyl derivative 39 {5-(3-cyclopropylpropyl)-
2-(difluoromethyl)-3H-pyrano[2,3-d]pyrimidine-4,7-dione}
mL h, 10 mg/kg po dosing).31 A head-to-head study between
3
39 and nicotinic acid demonstrated that 39 also had im-
proved potency compared to nicotinic acid in vitro and in
vivo (see Supporting Information). Compound 39 dose-depen-
dently inhibited rat plasma FFA with an ED50 of 0.2 mg/kg
and a maximally effective dose of 1.0 mg/kg. The ED50 for
nicotinic acid on plasma FFA was difficult to calculate due to
the steep dose response effect of nicotinic acid in this model.
The maximally effective dose for nicotinic acid on plasma
FFAwas 10 mg/kg. In addition, 39 dose-dependently lowered
plasma triglyceride 1 and 6 h after dosing in rats. In contrast,
nicotinic acid lowered plasma triglyceride in rats 1 h after
dosing but was not active at 6 h, indicating 39 had a longer
duration of action. A time course study of 39 in the rat at 3
mg/kg showed that it significantly reduced plasma triglycer-
ide from 1 to 8 h post dosing. In contrast, the duration of
activity with nicotinic acid at 10 mg/kg treatment did not
extend beyond 2 h after dosing. Compound 39 was
studied for efficacy and flushing profile in fasted male
beagle dogs. Although 39 had very similar in vitro potency
to nicotinic acid at dog GPR109a, it displayed much great-
er in vivo efficacy than nicotinic acid. Compound 39
exhibited dose-dependent inhibition of plasma FFA and
achieved 70% FFA reduction at 3 mg/kg dose. At this dose,
dogs had no overt signs of flushing, as determined by
quantification of changes in cutaneous blood flow (Figure 1)
and/or changes in skin color and behavior. In contrast,
nicotinic acid achieved similar reduction of FFA at 30 mg/
kg dose, but this dose produced a pronounced flushing
response in 9 of 13 dogs, observed as an average of a
5-fold increase in cutaneous blood flow from baseline
showed much improved potency relative to 31 (39; EC50
=
59 nM), but this was not the case for the cyclopropylbutyl
analogue 40. Introduction of a methyl substituent on the
r
2010 American Chemical Society
173
DOI: 10.1021/ml100251u ACS Med. Chem. Lett. 2011, 2, 171–176
|

pubs.acs.org/acsmedchemlett
Table 3. Potency of Compounds in the hu-GPR109a cAMP Assay
a Data represent an average of multiple determinations (n g 3) ( standard deviation.
Scheme 1. Synthesis of Compound 39a
a Reagents and conditions: (a) CHF2CO2Et, NaOEt, EtOH, reflux, 70-75%; (b) MeO2CCH2CO2K, CDI, MgCl2, THF, 85-95%; (c) HOAc, 120 °C,
20-25%.
(Figure 1) as well as behavioral responses characterized
by head shaking and ear scratching. Overall, 39 was
approximately 10-fold more potent than nicotinic acid in
reducing dog plasma FFA. At the effective dose, both the
r
2010 American Chemical Society
174
DOI: 10.1021/ml100251u ACS Med. Chem. Lett. 2011, 2, 171–176
|

pubs.acs.org/acsmedchemlett
Table 4. In Vitro and in Vivo Potencies of 39, 41, and Nicotinic Acid
39
41
nicotinic acid
hu-GPR109a EC50 (nM)a
59 ( 56
3 ( 1
49 ( 11
6 ( 2
100 ( 15
39 ( 10
29 ( 5
rat-GPR109a EC50 (nM)a
m-GPR109a EC50 (nM)a
4 ( 3
15 ( 5
126 ( 58
ndb
dog-GPR109a EC50 (nM)a
21 ( 4
2 ( 1
30 ( 14
26 ( 33
>10000
-80%c
-60%c
-38%
cyno-GPR109a (nM)a
hu-GPR109b EC50 (nM)a
300 ( 105
-77%
-49%
-70%
1120 ( 325
-14%
-23%
ndb
rat FFA reduction (1 h post 1 mg/kg dosing)
rat TG reduction (1 h post 1 mg/kg dosing)
dog FFA reduction (1 h post 3 mg/kg dosing)
a Data represent an average of multiple determinations (n g 3) ( standard deviation. b nd = not determined. c 10 mg/kg dosing.
AUTHOR INFORMATION
Corresponding Author: *Telephone: 908-740-3904. Fax: 908-
740-7664. E-mail:jun.qin@merck.com.
ACKNOWLEDGMENT We thank Drs. Pauline Ting, Christopher
Boyce, Michael Berlin, and James Tata for comments on the
preparation of the manuscript. We thank Drs. William Greenlee,
John Piwinski, and Catherine Strader for their strong support. We
thank Mary Senior and Li-Kang Zhang for technical support.
ABBREVIATIONS VLDL, very low-density lipoprotein; LDL,
low-density lipoprotein; LPa, lipoprotein-a; HDL, high-den-
sity lipoprotein; NA, nicotinic acid; TG, triglyceride; FFA, free
fatty acid; DP, prostaglandin D2 receptor; GPR, G-protein-
coupled receptor; cAMP, 30-50-cyclic adenosine monopho-
sphate.
Figure 1. Peak fold increase from baseline in cutaneous blood
flow in dogs dosed with 39 (0.1-3 mg/kg, po), nicotinic acid, or
vehicle (data for individual dogs).
severity and incidence of flushing were markedly reduced
or absent compared to the case of nicotinic acid. This
compound also demonstrated an acceptable PK profile in
REFERENCES
(1)
Altschul, R.; Hoffer, A.; Stephen, J. D. Influence of nicotinic
acid on serum cholesterol in man. Arch. Biochem. 1955, 54,
558–559.
dog (39 dog AUC0-24h=70.2 μg/mL h, 3 mg/kg po dosing).
3
Compound 39 had no effect on hERG at concentrations up
to 6 μM, was not an inhibitor of human CYPs 1A2, 2C9,
2D6, or 3A4 (IC50 > 50 μM), and did not show induction of
CYP3A4 in the human PXR assay up to 10 μM. No sig-
nificant activity was observed for 39 in the Cerep and
GPCR counterscreens. In the radioligand binding experi-
ment, the binding of compound 39 with GPR109a is
competitive with nicotinic acid.
(2)
(3)
Carlson, L. A. Nicotinic acid: the broad-spectrum lipid drug. A
50th anniversary review. J. Int. Med. 2005, 258, 94–114.
Gotto, A. M., Jr. Low high-density lipoprotein cholesterol as a
risk factor in coronary heart disease. Aworking group report.
Circulation 2001, 103, 2213–2218.
(4)
(5)
Boatman, P. D.; Richman, J. G.; Semple, G. Nicotinic acid
receptor agonists. J. Med. Chem. 2008, 51, 7653–7662.
Imbriglio, J. E.; Chang, S.; Liang, R.; Raghavan, S.; Schmidt,
D.; Smenton, A.; Tria, S.; Schrader, T. O.; Jung, J.; Esser, C.;
Taggart, A. K. P.; Cheng, K.; Carballo-Jane, E.; Waters, M. G.;
Tata, J. R.; Colletti, S. L. GPR109a agonists. Part 1: 5-Alkyl and
5-aryl-pyrazole-tetrazoles as agonists of the human orphan
G-protein coupled receptor GPR109a. Bioorg. Med. Chem. Lett.
2009, 19, 2121–2124.
In summary, we have identified a potent nicotinic acid
receptor agonist 39, which demonstrated excellent in vivo
activity in animal models. In addition, the incidence and
magnitude of cutaneous blood flow increases observed with
nicotinic acid in the dog models were not observed with
compound 39, suggesting that it has an improved therapeutic
window to flushing compared to nicotinic acid. This compound
was investigated and developed further for its clinical potential.
These results will be the subject of future publications.
(6)
(7)
Boatman, P. D.; Schrader, T. O.; Kasem, M.; Johnson, B. R.;
Skinner, P. J.; Jung, J.; Xu, J.; Cherrier, M. C.; Webb, P. J.;
Semple, G.; Sage, C. R.; Knudsen, J.; Chen, R.; Taggart, A. K.;
Carballo-Jane, E.; Richman, J. G. Potent tricyclic pyrazole
tetrazole agonists of the nicotinic acid receptor (GPR109a).
Bioorg. Med. Chem. Lett. 2010, 20, 2797–2800.
Imbriglio, J. E.; Chang, S.; Liang, R.; Raghavan, S.; Schmidt,
D.; Smenton, A.; Tria, S.; Schrader, T. O.; Jung, J.; Esser, C.;
Holt, T. G.; Wolff, M. S.; Taggart, A. K. P.; Cheng, K.; Carballo-Jane,
SUPPORTING INFORMATION AVAILABLE Experimental
procedures for assay protocols, in vivo studies, and synthesis and
characterization of compounds 1-47. This information is available
free of charge via the Internet at http://pubs.acs.org.
r
2010 American Chemical Society
175
DOI: 10.1021/ml100251u ACS Med. Chem. Lett. 2011, 2, 171–176
|

pubs.acs.org/acsmedchemlett
E.; Waters, M. G.; Tata, J. R.; Colletti, S. L. GPR109a agonists. Part
2: Pyrazole-acids as agonists of the human orphan G-protein
coupled receptor GPR109a. Bioorg. Med. Chem. Lett. 2010, 20,
4472–4474.
The Coronary Drug project: design, methods, and baseline
results. Circulation, 1973, 47, 1-179.
Canner, P. L.; Berge, K. G.; Wenger, N. K.; Stamler, J.; Friedman,
L.; Prineas, R, J.; Friedewald, W. Fifteen year mortality in
Coronary Drug Project patients: long term benefit with niacin.
J. Am. Coll. Cardiol. 1986, 8, 1245–1255.
nicotinic acid and mediate its antilipolytic effect. Nat. Med.
2003, 9, 352–355.
(23) 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.
(8)
(9)
€
(24) Carlson, L. A.; Oro, 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.
(25) 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.
(10) Brown, B. G.; Zhao, X. Q.; Chait, A.; Fisher, L. D.; Cheung,
M. C.; Morse, J. S.; Dowdy, A. A.; Marino, E. K.; Bolson, E. L.;
Alaupovic, P.; Frohlich, J.; Albers, J. J. Simvastatin and
niacin, antioxidant vitamins, or the combination for the
prevention of coronary disease. N. Eng. J. Med. 2001, 345,
1583–1592.
(11) Taylor, A. J.; Sullenberger, L. E.; Lee, H. J.; Lee, J. K.; Grace, K. A.
Arterial Biology for the Investigation of the Treatment Effects
of Reducing Cholesterol (ARBITER) 2: a double-blind, place-
bo-controlled study of extended-release niacin on athero-
sclerosis progression in secondary prevention patients treated
with statins. Circulation 2004, 110, 3512–3517.
(26) Carlson, L. A.; Hanngren, A. Initial distribution in mice of 3H-
labeled nicotinic acid studied with autoradiography. Life Sci.
1964, 3, 867–871.
(27) Butcher, R. W.; Baird, C. E.; Sutherland, E. W. Effects of
lipolytic and antilipolytic substances on adenosine 30, 50-
monophosphate levels in isolated fat cells. J. Biol. Chem.
1968, 243, 1705–1712.
(28) Aktories, K.; Schultz, G.; Jakobs, K. H. Regulation of adenylate
cyclase activity in hamster adipocites. Inhibition by prosta-
glandins, R-adrenergic agonists and nicotinic acid. Naunyn-
Schmiedeberg's Arch. Pharmacol. 1980, 312, 167–173.
(29) Sprecher, D. L. Raising high-density lipoprotein cholesterol
with niacin and fibrates: a comparative review. Am. J. Cardiol.
2000, 86, 46–50.
(30) 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.
(31) Korfmacher, W. A.; Cox, K. A.; Ng, K. J.; Veals, J.; Hsieh, Y.;
Wainhaus, S.; Broske, L.; Prelusky, D.; Nomeir, A.; White, R. E.
Cassette-accelerated rapid rat screen: a systematic procedure
for the dosing and liquid chromatography/atmospheric pres-
sure ionization tandem mass spectrometric analysis of new
chemical entities as part of new drug discovery. Rapid Com-
mun. Mass Spectrom. 2001, 15, 335–340.
(12) 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.
(13) Hiatt, J. G.; Shamsie, S. G.; Schectman, G. Discontinuation
rates of cholesterol-lowering medications: implications for
primary care. Am. J. Manag. Care 1999, 5, 437–444.
(14) Knopp, R. H.; Ginsberg, J.; Albers, J. J.; Hoff, C.; Ogilvie, J. T.;
Warnick, G. R.; Burrows, E.; Retzlaff, B.; Poole, M. Contrasting
effects of unmodified and time-release forms of niacin on
lipoproteins in hyperlipidemic subjects: clues to mechanism
of action of niacin. Metabolism 1985, 34, 642–650.
(15) Dalton, T. A.; Berry, R. S. Hepatotoxicity associated with
sustained-release niacin. Am. J. Med. 1992, 93, 102–104.
(16) Lawrence, S. P. Transient focal hepatic defects related to
sustained-release niacin. J. Clin. Gastroenterol 1993, 16,
234–236.
(17) Etchason, J. A.; Miller, T. D.; Squires, R. W.; Allison, T. G.; Gau,
G. T. Niacin-induced hepatitis: a potential side effect with low-
dose time-release niacin. Mayo Clin. Proc. 1991, 66, 23–28.
(18) Morgan, J. M.; Capuzzi, D. M.; Guyton, J. R.; Centor, R. M.;
Goldberg, R.; Robbins, D. C.; Dipette, D.; Jenkins, S.;
Marcovina, S. Treatment effects of Niaspan, a controlled-
release niacin, in patients with hypercholesterolemia: a placebo-
controlled trial. J. Cardiovasc. Pharmacol. Ther. 1996, 1,
195–202.
(19) 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.
(20) 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.
(21) 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.
(22) Tunaru, S.; Kero, J.; Schaub, A.; Wufka, C.; Blaukat, A.; Pfeffer,
K.; Offermanns, S. PUMA-G and HM74 are receptors for
r
2010 American Chemical Society
176
DOI: 10.1021/ml100251u ACS Med. Chem. Lett. 2011, 2, 171–176
|