Discovery of SCH 900271, a potent nicotinic acid receptor agonist for the treatment of dyslipidemia

Article abstract of DOI:10.1021/ml200243g

Structure-guided optimization of a series of C-5 alkyl substituents led to the discovery of a potent nicotinic acid receptor agonist SCH 900271 (33) with an EC₅₀ of 2 nM in the hu-GPR109a assay. Compound 33 demonstrated good oral bioavailability in all species. Compound 33 exhibited dose-dependent inhibition of plasma free fatty acid (FFA) with 50% FFA reduction at 1.0 mg/kg in fasted male beagle dogs. Compound 33 had no overt signs of flushing at doses up to 10 mg/kg with an improved therapeutic window to flushing as compared to nicotinic acid. Compound 33 was evaluated in human clinical trials.

Full text of DOI:10.1021/ml200243g

Letter
pubs.acs.org/acsmedchemlett
Discovery of SCH 900271, a Potent Nicotinic Acid Receptor Agonist
for the Treatment of Dyslipidemia
Anandan Palani,*,† Ashwin U. Rao,*,† Xiao Chen,† Xianhai Huang,† Jing Su,† Haiqun Tang,†
Ying Huang,† Jun Qin,† Dong Xiao,† Sylvia Degrado,† Michael Sofolarides,† Xiaohong Zhu,† Zhidan Liu,†
Brian McKittrick,† Wei Zhou,† Robert Aslanian,† William J. Greenlee,† Mary Senior,†
Boonlert Cheewatrakoolpong,‡ Hongtao Zhang,‡ Constance Farley,‡ John Cook,‡ Stan Kurowski,‡
Qiu Li,‡ Margaret van Heek,‡ Gangfeng Wang,§ Yunsheng Hsieh,§ Fangbiao Li,§ Scott Greenfeder,‡
and Madhu Chintala‡
‡
§
†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
S
* Supporting Information
ABSTRACT: Structure-guided optimization of a series of C-5 alkyl substituents led to the discovery of a
potent nicotinic acid receptor agonist SCH 900271 (33) with an EC50 of 2 nM in the hu-GPR109a assay.
Compound 33 demonstrated good oral bioavailability in all species. Compound 33 exhibited dose-
dependent inhibition of plasma free fatty acid (FFA) with 50% FFA reduction at 1.0 mg/kg in fasted male
beagle dogs. Compound 33 had no overt signs of flushing at doses up to 10 mg/kg with an improved
therapeutic window to flushing as compared to nicotinic acid. Compound 33 was evaluated in human
clinical trials.
KEYWORDS: Nicotinic acid receptor (NAR) agonist, flushing, dyslipidemia, FFA, LDL-C, VLDL-C, TG, HDL-C, CAD
orbidity and mortality associated with coronary artery
disease (CAD) are significant problems around the
and is only expressed in the human and chimpanzee.12−16
Activation of GPR109a in adipose tissue mediates an
antilipolytic response by lowering intracellular 3′-5′-cyclic
adenosine monophosphate (cAMP) levels, leading to reduced
protein kinase A activity. This in turn results in a decrease in
lipase activity and a reduction in intracellular TG hydrolysis. A
reduction in intracellular lipolysis decreases FFA secretion into
plasma and ultimately reduces the hepatic FFA pool available
for TG resynthesis. It has been postulated that the decreased
availability of FFA in the liver directly reduces the production
of hepatic TG and VLDL.17−21 What is much less clear is
whether the acute effects on plasma FFA and TG can
eventually lead to an increase in HDL-C levels and other
associated lipid and lipoprotein changes.22,23
Since the discovery of NA receptors (NAR), extensive efforts
have been devoted to NAR agonists.24−27 Our lead
identification strategy, which involved an extensive structure−
activity relationship (SAR) investigation of the C-2 region of a
thiobarbituric acid core, had been shown to activate the
receptor and has been reported previously.28 Further screening
and elaboration of both the C-2 and the C-5 regions provided a
pyranopyrimidinedione series suitable for optimization as NAR
agonists. A comparison of the in vitro activity data of the
compounds synthesized is shown in Table 1. When the thiol
M
world. Elevated low-density lipoprotein cholesterol (LDL-C)
and plasma triglycerides (TG) and low levels of high-density
lipoprotein cholesterol (HDL-C) are considered risk factors for
the development of CAD. An improvement in all of these risk
factors would reduce the risk for developing CAD. Nicotinic
acid (NA, niacin) has been used clinically for decades to
favorably alter plasma lipids.1 NA reduces plasma free fatty acid
(FFA), very low-density lipoprotein cholesterol (VLDL-C),
LDL-C, plasma TG, and lipoprotein a (Lp-a), while increasing
HDL-C.2−7 Despite this attractive profile, physician adoption
and patient compliance with NA are limited due to intense
cutaneous flushing at therapeutic concentrations, a difficult
dose titration schedule to avoid this side effect, and large
doses.8,9 An extended release formulation of NA (NIASPAN) is
available by prescription.10 This formulation has a reduced
incidence of flushing, but patients must undergo a complicated
titration schedule to approach maximally efficacious doses and
often do not achieve desired lipid goals due to tolerability
issues. In addition, studies have shown that patients taking a
combination of extended release NA and an antagonist of the
prostaglandin D2 antagonist (DP) (TREDAPTIVE) show
reduced flushing symptoms as compared to taking NA alone.11
The molecular target for NA was discovered in 2003. NA
binds with high affinity to and activates the G-protein coupled
receptor GPR109a, expressed primarily in human adipose
tissue. NA also binds with low affinity to the homologous
receptor GPR109b, which shares ∼95% identity to GPR109a
Received: October 15, 2011
Accepted: November 24, 2011
Published: November 24, 2011
© 2011 American Chemical Society
63
dx.doi.org/10.1021/ml200243g | ACS Med. Chem. Lett. 2012, 3, 63−68

ACS Medicinal Chemistry Letters
Letter
Table 1. Potency of Compounds in the hu-GPR109a cAMP Assay
a
a
compd
R1
Et
EC50 (nM)
compd
R1
EC50 (nM)
1600 720
>10000
>10000
930 230
1
2
3
4
5
6
31 18
290 14
99 58
7
8
CH2CF3
Me
Ph
n-Pr
n-Bu
i-Pr
CF3
9
CO2Me
17 5.0
220 44
>10000
10
11
12
CH2CO2Me
4−F-C6H4CH2
CH(OH)Me
170 54
1300 240
a
Data represent an average of multiple determinations (n ≥ 3) standard deviations.
Table 2. Potency of Compounds in the hu-GPR109a cAMP Assay
a
Data represent an average of multiple determinations (n ≥ 3) standard deviations.
group (vide supra) was changed to a carbonyl group (1), while
maintaining the ethyl group at the C-5 position, significant
improvement in potency was observed. Compounds 2 and 3,
incorporating methyl and n-propyl groups, respectively, were
3−9-fold less active in the cAMP assay. Interestingly, the
n-butyl analogue 4 showed moderate activity equivalent to that
of 1. Changing R1 from ethyl (1) to isopropyl (5) was less
tolerated, with 7-fold loss in activity. Fluoroalkyl derivatives
were less tolerated with significant loss in activity (6 and 7).
When R1 was substituted with phenyl (8) or an ester (9), there
was complete loss in activity. One carbon homologation of 8
and 9 as in 10 and 11 or introduction of polar functional group
(12) resulted in decreased activity.
chain with different alkyl and aryl substituents (Table 2).
Although the phenyl group in 13 had a negative effect on
activity, the thiophene derivatives (14 and 15) retained better
in vitro activity. Compounds 16 and 17 with longer alkyl side
chains retained activity similar to that of 4. Introduction of
heteroatoms, for example 18, showed much weaker activity,
whereas the thio analogue 19 showed excellent activity.
However, oxidation of 19 to the sulfone 20 was detrimental
to activity. Meanwhile, the effect of branching on compound 4
was studied, which showed some interesting results. The α- and
β-methyl group (with respect to C-5) in 21 and 22 showed
significant loss in potency, while the γ-methyl improved the
potency in the hu-GPR109a assay by 4-fold (23, EC50 = 4.0
nM). Introduction of another methyl substituent at the gamma
position (24) resulted in complete loss of activity, indicating
Having identified the optimal R1 linker length, we undertook
additional SAR studies on the C-5 region having longer side
64
dx.doi.org/10.1021/ml200243g | ACS Med. Chem. Lett. 2012, 3, 63−68

ACS Medicinal Chemistry Letters
Letter
a
Scheme 1. Synthesis of Compound 33
a
Reagents and conditions: (a) Et2Zn, CH2I2, TFA, CH2Cl2, 0 °C to room temperature, 12 h, 99%. (b) NaOH, EtOH, room temperature, 12 h, 93%.
(c) Ethyl potassium malonate, CDI, MgCl2, THF, room temperature, 12 h, 99%. (d) Compound 41, glacial AcOH, 110 °C, 24 h, 15%.
Table 3. In Vitro and in Vivo Potencies of NAR Agonists and NA
4
23
4.0
26
3.0
29
1.0
30
4.0
33
NA
a
a
hu-GPR109a EC50 (nM)
17
2.0
99 15
>10000
hu-GPR109b EC50 (nM)
190
8.0
1300
4.0
59
67
140
2.0
96
a
rat-GPR109a EC50 (nM)
2.0
5.0
3.0
ND
5.0
4.0
ND
8.0
39 10
29 5.0
31 13
a
b
b
m-GPR109a EC50 (nM)
dog-GPR109a EC50 (nM)
12
ND
ND
1.0
6.0
a
b
b
16
ND
5.0
c
b
d
rat FFA reduction (1 h post 1.0 mg/kg dosing) (%)
rat TG reduction (1 h post 1.0 mg/kg dosing) (%)
dog FFA reduction (1 h post 1.0 mg/kg dosing) (%)
−29
−40
−90
−15
−50
−31
ND
−58
−49
−80
c
−53
−53
−50
−80
c
d
−16
−59
−80
−60
e
b
c
b
f
c
ND
−38
a
b
d
Data represent an average of multiple determinations (n ≥ 3) standard deviations. ND, not determined. 3.0 mg/kg dosing. 10.0 mg/kg
e
f
dosing. 0.3 mg/kg dosing. 2.0 mg/kg dosing.
the role of steric hindrance in cAMP activity. Homologation of
23 to 25 retained the best in vitro activity with an EC50 of 5.0
nM. Interestingly, fluoroalkyl derivatives 26 and 27 showed
good activity with the difluoromethyl analogue (26) having an
EC50 of 3.0 nM. An attempt was made to introduce small
cycloalkyl groups given the promising data of analogues 23 and
25. The cyclopropyl ring (28) was 3-fold less potent than 23.
However, the cyclobutyl ring (29) showed excellent activity
(EC50 = 1.0 nM). Increasing the linker length had an opposite
effect on activity (30, EC50 = 4.0 nM, vs 31, EC50 = 39 nM).
Further extending the linker length (32) led to decreased
activity. Elaboration of SAR on compound 30 with substituents
on the cyclopropyl ring was investigated with the identification
with ethyl 5-methylhex-5-enoate 37, cyclopropanation followed
by basic hydrolysis afforded 4-(1-methylcyclopropyl)butanoic
acid 39. The acid 39 was then converted to the β-keto ester 40
followed by condensation of barbituric acid 41 in refluxing
acetic acid to afford 33. This sequence was adopted to prepare
most of the analogues in this series.
Following these initial studies, several compounds were
dosed orally in a rat in vivo model designed to measure
reductions in FFA and TG (Table 3). Compound 4
demonstrated excellent efficacy in vivo (rat FFA, −29%; TG,
−40%, 1 h post 1.0 mg/kg po dosing). Compound 4 also
exhibited a dose-dependent reduction in plasma FFA and
achieved 90% FFA reduction at 0.3 mg/kg dose in dogs. Only a
very modest reduction of FFA and TG was observed following
oral administration of 3.0 mg/kg of 23, which was not
statistically significant. Excellent in vivo efficacy was observed
with compound 26 (TG, −59%, 1 h post 1.0 mg/kg po
dosing). In dogs, 26 suppressed plasma FFA (80%); however, 4
h postdosing, FFA rebounded to levels markedly above
baseline, a phenomenon not seen with other compounds in
this series. The observed FFA reduction was also accompanied
by modest flushing seen at 3.0 mg/kg also not seen with other
compounds in this series. It is of interest to note the potential
link between flushing and FFA rebound with compound 26,
which is reminiscent of the clinical profile of niacin. The reason
for flushing behavior shown by compound 26 is not clear, and
we speculate that it could be due to differences in free drug
of compound SCH 900271 (33) with excellent activity (EC50
=
2.0 nM). The substitution on the ipso position of cyclopropyl
played an important role in activity, although the ethyl (34)
and the halogens (35 and 36) showed a slight decrease in
activity. SAR studies of the C-5 region eventually led to the
discovery of several compounds with potent in vitro activity.
Compounds tested active as GPR109a agonists are full agonists
and showed much weaker agonist potency for the GPR109b
(vide infra). The presence of the NH is important for GPR109a
activity, and the acidic N1−H bond mimics the role of NA. The
substitution of small alkyl groups on either N1 or N3 led to
several fold loss in agonist potency.29
The synthetic route to pyranopyrimidinedione 33 as a
representative example is summarized in Scheme 1. Starting
65
dx.doi.org/10.1021/ml200243g | ACS Med. Chem. Lett. 2012, 3, 63−68

ACS Medicinal Chemistry Letters
Letter
concentration in plasma.30 Reduction of FFA and TG levels by
29 and 30 was also measured in rats and dogs. Significant
reductions in plasma FFA and TG were observed that were
essentially equal in magnitude to the response elicited by a 10
mg/kg dose of NA. However, further evaluation of compound
4 was discontinued as it was found to cause acute renal necrosis
in mice. Serum blood urea nitrogen (BUN) and creatinine were
markedly elevated in mice at 100 mg/kg. Profound
nephrotoxicity was also observed with a few other compounds
in this series, including compounds 29 and 30. Similar toxicity
was not observed in rats, thereby suggesting that this
phenomenon is likely species specific. The mechanism of this
observed side effect is yet to be determined. Compound 33 was
profiled further to assess its potential as a drug candidate.
Additionally, compound 33 was assessed for the reduction in
FFA and TG in fasted rats (Table 3). Compound 33 was dosed
orally in fasted rats, which demonstrated robust efficacy in vivo
(rat FFA, −53%; TG, −53%, 1 h post 1.0 mg/kg po dosing) as
compared to 4. Compound 33 had good plasma exposure in rat
AUC0−24 h = 7.6 μM h, 5 mg/kg po dosing, and F = 76%. A
head-to-head study between 33 and NA demonstrated that 33
also had improved potency as compared to NA in vitro and in
vivo (see the Supporting Information). Compound 33 dose
dependently reduced rat plasma FFA and TG with an ED50 of
approximately 0.5 mg/kg and a maximally effective dose of 3.0
mg/kg. The ED50 for NA on plasma FFA was difficult to
calculate due to its steep dose response effect in this model.
The maximally effective dose for NA on plasma FFA was 10
mg/kg. A time−course study of 33 in rat at 3.0 mg/kg showed
that it reduced FFA and plasma TG 0.5, 1, and 2 h after dosing
but had no activity at later time points. In comparison, the
duration of activity with NA at 10 mg/kg treatment did not
extend beyond 2 h after dosing. Compound 33 was studied for
efficacy and flushing profile in fasted male beagle dogs and
exhibited dose-dependent inhibition of plasma FFA with 50%
FFA reduction at 1.0 mg/kg (Figure 1). At this dose and up to
10 mg/kg, dogs had no overt signs of flushing, as determined
by quantification of changes in cutaneous blood flow and/or
changes in skin color and behavior (Figure 2). In contrast, NA
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 as well as behavioral responses characterized
by head shaking and ear scratching. There was no incidence of
nephrotoxicity with 33 in mice at 100 mg/kg po for 5 days.
This compound also demonstrated a good pharmacokinetic
(PK) profile in the dog (dog AUC0−24 h = 7.2 μM h, 1.0 mg/kg
po dosing, and F = 40%). Compound 33 had no effect on
hERG at concentrations up to 10 μM,31 representing a 1400-
fold multiple of the projected free human Cmax required for
efficacy, 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 significant
activity was observed for 33 in various counter screens. The
CLint value of compound 33 in human/rat/dog/mouse is 1.6/
10/<1/8.7 μL/min/106 cells.
In summary, we have identified a potent NAR agonist 33,
which demonstrated excellent in vivo activity in animal models.
In addition, the incidence and magnitude of cutaneous blood
Figure 1. Acute FFA reduction of compound 33 in dogs.
Figure 2. Peak fold increase from baseline in cutaneous blood flow in dogs dosed with compound 33 (0.3−10 mg/kg, po), NA, or vehicle (data for
individual dogs).
66
dx.doi.org/10.1021/ml200243g | ACS Med. Chem. Lett. 2012, 3, 63−68

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://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
(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.
palani@merck.com (A.P.). Tel: 908-740-5527. Fax: 908-740-
7664. E-mail: ashwin.rao@merck.com (A.U.R.).
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.
■
(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.
■
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.
67
dx.doi.org/10.1021/ml200243g | ACS Med. Chem. Lett. 2012, 3, 63−68

ACS Medicinal Chemistry Letters
Letter
(29) The EC50 in the hu-GPR109a assay of N1 and N3 methyl
analogues of compound 30 are 2700
1500 and 250
56 nM,
respectively.
(30) We compared both flushing and non-flushing compounds in in
vitro macrophage models to evaluate the ability to elicit the release of
prostaglandin (a key driver of flushing).2,8,11 No difference was found
in that all compounds tested elicited the release of prostaglandins to a
similar degree (data not shown). Given the similar activity of these
compounds to cause release of a potential driver of flushing
(prostaglandin), we speculate that the differences between compounds
in this series to cause flushing are more likely related to
physicochemical and/or pharmacokinetic properties. In dogs, the
free drug concentration (at tmax) in plasma of compound 26 is 206.2
ng/mL and 83.9% protein bound whilst the free drug concentration
for 33 is 26.1 ng/mL and 99% protein bound.
(31) Finkel, A.; Wittel, A.; Yang, N.; Handran, S.; Hughes, J.;
Costantin, J. Population patch clamp improves data consistency and
success rates in the measurement of ionic currents. J. Biomol. Screening
2006, 11, 488−496.
(32) Study ID NCT00941603. Available from www.clinicaltrials.gov.
68
dx.doi.org/10.1021/ml200243g | ACS Med. Chem. Lett. 2012, 3, 63−68