Discovery of biaryl anthranilides as full agonists for the high affinity niacin receptor

Article abstract of DOI:10.1021/jm700942d

Biaryl anthranilides are reported as potent and selective full agonists for the high affinity niacin receptor GPR109A. The SAR presented outlines approaches to reduce serum shift and both CYPCYP2C8 and CYP2C9 liabilities, while improving PK and maintainin

Full text of DOI:10.1021/jm700942d

J. Med. Chem. 2007, 50, 6303–6306
6303
Scheme 1
Discovery of Biaryl Anthranilides as Full
Agonists for the High Affinity Niacin
Receptor
Hong C. Shen,* Fa-Xiang Ding, Silvi Luell,
Michael J. Forrest, Ester Carballo-Jane, Kenneth K. Wu,
Tsuei-Ju Wu, Kang Cheng, Larissa C. Wilsie,
Mihajlo L. Krsmanovic, Andrew K. Taggart, Ning Ren,
Tian-Quan Cai, Qiaolin Deng, Qing Chen, Junying Wang,
Michael S. Wolff, Xinchun Tong, Tom G. Holt,
M. Gerard Waters, Milton L. Hammond, James R. Tata, and
Steven L. Colletti
Regarding niacin’s mechanism of action, it is known that
niacin binds to GPR109A found on adipocytes and decreases
the hydrolysis of adipocyte TG, thereby resulting in a transient
reduction of plasma free FFA concentration. There has been a
hypothesis in the literature that the reduction of FFA leads to
sustained plasma TG reduction and HDL-C elevation. Moreover,
because GPR109A is also expressed on immune cells, it is
possible that some of its antiatherosclerotic effects derive from
Merck Research Laboratories, Merck & Co., Inc.,
Rahway, New Jersey 07065-0900
ReceiVed July 31, 2007
Abstract: Biaryl anthranilides are reported as potent and selective full
agonists for the high affinity niacin receptor GPR109A. The SAR
presented outlines approaches to reduce serum shift and both
CYPCYP2C8 and CYP2C9 liabilities, while improving PK and
maintaining excellent receptor activity. Compound 2i exhibited good
in vivo antilipolytic efficacy while providing a significantly improved
therapeutic index over vasodilation (flushing) with respect to niacin in
the mouse model.
3b
modulation of vascular inflammation.
To measure the activity of our compounds against GPR109A,
a [3H]-niacin competition binding assay in either the absence
or the presence of 4% human serum and a guanine nucleotide
exchange assay (GTPγS) were employed. In both assays,
membranes from CHO cells expressing the recombinant human
GPR109A were utilized. All active analogs described in this
paper had a similar maximum level of response as niacin in the
GTPγS assay and were, therefore, characterized as full agonists.
High-throughput screening identified compound 1a as a hit with
moderate activity (Table 1). A rapid optimization led to the
discovery of compound 1b with improved activity similar to
niacin in both binding and hGTPγS assays. It was then
envisioned that the methoxyphenyl group in 1a or naphthyl
group of 1b could be replaced by a biphenyl structure, thus
providing a readily accessible and modular scaffold (Scheme
1). Indeed, biphenyl analog 1c showed similar activity against
human GPR109A ([3H]-niacin IC50 ) 93 nM and hGTPγS EC50
) 0.59 µM) as niacin. The SAR on the length of the linker
between the amide and the biphenyl moiety, the alignment
pattern of the biphenyl group, and the SAR surrounding both
the inner and the terminal phenyl group led to a potent analog
1d ([3H]-niacin IC50 ) 4 nM and hGTPγS EC50 ) 0.045 µM).
Despite its excellent activity, 1d suffered from poor bioavail-
ability, high clearance, low oral exposure, high serum shift
(∼8000-fold), and potent CYP2C8 and 2C9 inhibition (EC50
< 0.4 µM for both enzymes). To overcome these issues that
were common for the biphenyl class, biaryl anthranilides
containing one or two heterocycles were discovered.
The terminal and inner rings of the biaryl system were
systematically modified and studied for their impact on activity
and serum shift (Tables 1–3). A subset of these compounds were
tested and found inactive against GPR109B and GPR81
indicating that they were selective for GPR109A. Several
compounds were further profiled in CYP2C8 and 2C9 inhibition
assays (Table 4), and mouse PK studies (Table 5).
First, after systematic modification of the terminal ring with
various pyridine, pyrimidine, and pyrazine regioisomers (data
not shown), analog 2a gave the best activity matching that of
the niacin control. The installation of the terminal hydroxyl
group (2b) improved the affinity 10-fold. However, the large
serum shift of 2b had to be reduced. The amino substitution at
Niacin (nicotinic acid, Scheme 1), a group B vitamin, serves as
a precursor for NAD+ and NADP+ and is physiologically active
at >15–20 mg/day.1 As an antidyslipidemic drug dosed 500–2000
mg/day, niacin demonstrates its pharmacological utility by modify-
ing various lipid profiles.2 Particularly, niacin elevates HDL-C,a
reduces total plasma cholesterol, TG, VLDL-C, LDL-C, and Lp(a).3
In a series of clinical studies, including the Coronary Drug Project
(CDP),4 Stockholm Ischemeic Heart Disease Study,5 HATS trial,6
and ARBITER 2 trial, 7 niacin significantly decreased the morbidity
and mortality of patients with coronary heart disease and slowed
the progression of atherosclerosis by monotherapy or combination
therapy with simvastatin. However, cutaneous flushing is a major
adverse effect of niacin therapy, which results in lowered patient
compliance.
GPR109A (HM74A in humans and PUMA-G in mice), the
high affinity niacin receptor, was recently discovered.8 Coupled
to Gi proteins, GPR109A is expressed mainly on adipocytes
and immune cells. Two other receptors related to GPR109A
are GPR109B and GPR81. Interestingly, niacin has over a 1000-
fold higher affinity for GPR109A than GPR109B despite the
high identity between these two receptors (∼90%). Niacin is
not active against GPR81, which has <50% identity with
GPR109A and GPR109B. Given the beneficial role of niacin,
the discovery of GPR109A has stirred the interests of both
academia9 and the pharmaceutical industry10 in pursuing ago-
nists as potential therapeutic agents for cardiovascular disease
devoid of the side effects of niacin.
* To whom correspondence should be addressed. Phone: 732-594-1755.
Fax: 732-594-9473 . E-mail: hong_shen@merck.com.
aAbbreviations: CYP, cytochrome P450; HDL-C, high density lipoprotein
cholesterol; TG, triglyceride; VLDL-C, very low-density lipoprotein
cholesterol; LDL-C, low-density lipoprotein cholesterol; Lp(a), lipoprotein
a; PUMG-G, protein-upregulated in macrophages by interferon γ; FFA,
free fatty acid; CHO, Chinese hamster ovary; SAR, structure–activity
relationship; DMAP, 4-dimethylaminopyridine; PK, pharmacokinetics; PD,
pharmacodynamics.
10.1021/jm700942d CCC: $37.00
2007 American Chemical Society
Published on Web 11/10/2007

6304 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 25
Letters
Table 1. In Vitro SAR of Biaryl Anthranilide Analogs to Optimize the
Table 3. In Vitro SAR of Biheteroaryl Anthranilide Analogs for Human
Terminal Ring for Human GPR109Aa
GPR109Aa
a On average, repeat determinations differed by 120%. b The binding
assay was performed in the presence of 4% of human serum to calculate
the serum shift.
a On average, repeat determinations differed by 120%. b The binding
assay was performed in the presence of 4% of human serum to calculate
the serum shift.
Table 2. In Vitro SAR of Biaryl Anthranilide Analogs Containing an
Inner Heterocycle for Human GPR109Aa
Table 4. Human CYP2C8 and 2C9 Inhibition Profilesa
cmpd
CYP2C8, IC50 (µM)
CYP2C9, IC50 (µM)
1d
2b
2g
2h
2l
2m
2o
<0.4
8.9
1.2
19
20.3
9.3
<0.4
1.6
2.8
15
5.7
4.2
42
>100
a The CYP2C8 inhibition assay in human liver microsomes used taxol
and montelukast as the substrate and positive control, respectively. The
CYP2C9 inhibition assay in human liver microsomes used diclofenac and
sulfaphenazole as the substrate and positive control, respectively.
triazole, 1,2,4-triazole, 1,2,4-oxadiazole, or 1,3,4-oxadiazole as
the inner ring, and compounds 2h and 2i were identified for
their relatively low serum shift and good activity. In the human
adipocyte assay in which the inhibition of lipolysis in human
adipocytes was measured, 2h and 2i reduced FFA more
effectively than niacin. Interestingly, 2j, a regioisomer of 2i,
was 30-fold less active against GPR109A.
Lastly, our attention was turned to biheteroaryl analogs (Table
3). Hydroxypyrazole 2k recapitulated the finding that a terminal
hydroxyl group improved affinity. The combination of the
optimized hydroxypyridine as the terminal ring, and the inner
heterocycles with good properties in Table 2, produced thiazole
(2l and 2m) and pyrazole (2n) analogs with modest activities
and over 100-fold serum shift. In contrast, compound 2o
displayed low nanomolar activity and a much lower serum shift
(∼30 fold). In the human adipocyte assay, 2o effectively
suppressed lipolysis with a 10-fold greater activity than niacin.
Not only did the lead compound 1d have issues with serum
shift, it was also a potent inhibitor of both CYP2C8 and 2C9
isozymes. Guided by the SAR, polar heterocycles helped to
eliminate CYP liabilities.
a On average, repeat determinations differed by 120%. b The binding
assay was performed in the presence of 4% of human serum to calculate
the serum shift.
the same position of a hydrogen bond donor (2c) resulted in a
loss of activity. Five-membered heterocycles such as isoxazole
(2d) and pyrole (2e) were inferior compared to 2a.
Then the inner heterocycle was explored (Table 2). The
thiophene isostere of the phenyl group (2f) yielded a marginal
improvement of the serum shift yet similar activity compared
to 1d.
More polar heterocycles were designed to attempt to reduce
serum shift. Indeed, thiazole analog 2g lowered the serum shift
to 340-fold and offered single digit nanomolar activity in the
binding and functional assays. Next we examined compounds
containing pyrazole, imidazole, isoxazole, oxazole, 1,2,3-
The replacement of the terminal phenol with a hydroxypy-
ridine (2b) or the inner phenyl group with a thiazole (2g)
reduced both CYP2C8 and 2C9 inhibition (Table 4) compared
to 1d. The combination of hydroxypyridine and thiazole (2l and
2m) was synergistic on reduction of CYP2C8 and 2C9 inhibition

Letters
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 25 6305
Table 5. Mouse PK Profilesa
cmpd
F%
Cl (mL/min /kg)
Vdss (L/kg)
Cmax (µM)
T1/2 (h)
AUCpo(µM·h·kg/mg)
1d
2b
2g
2h
2i
5
57
37
2.5
6
18
0.38
7.3
26
34
8.5
0.35
0.11
0.37
0.88
1.66
0.62
0.96
5.0
2.1
0.03
0.12
0.52
2.0
5.3
1.6
1.1
1.3
2.2
0.11
15
2.1
0.1
0.18
1.5
2l
27
a Values are an average of three mice. IV dose, 1 mg/kg; PO dose, 2 mg/kg. Vehicle: DMSO/PEG400/water (5:40:55 v:v:v).
Figure 1. The FFA lowering effect of 2i and niacin by p.o. dosing
(mpk ) mg/kg). Compound 2i for mouse GPR109A: 3H-niacin binding
IC50 ) 0.46 µM, GTPγS EC50 ) 1.6 µM; niacin for mouse GPR109A:
3H-niacin binding IC50 ) 0.14 µM, GTPγS EC50 ) 0.27 µM.
Compound and FFA plasma levels were measured at 15 min post-
dosing.
and gave higher IC50s for both enzymes. The pyrazole ring was
Figure 2. The mouse ear vasodilation effect of 2i and niacin (i.p.
dosing) in 5% DMSO/40% PEG400/55% water (mpk ) mg/kg).
unique in that the IC50s of 2h against CYP2C8 and 2C9 were
above 10 µM for both enzymes despite the presence of the
phenol group. Compound 2o completely eliminated the CYP2C8
and 2C9 inhibition concern by incorporating the hydroxypyri-
dine and 1,3,4-oxadiazole combination.
In addition to its good activity, 2b has a remarkable PK profile
(Table 5) in sharp contrast to 1d. As the most potent compound
in this report, 2g also provided a good PK profile exemplified
by lower clearance, higher AUC, and bioavailability than 1d.
Compounds 2h and 2i represented breakthroughs in serum shift
but were inferior in PK with poor bioavailability, high clearance,
and low oral exposure. It was suspected that the presence of
the phenol might be detrimental based upon the observation of
the superior PK of 2b over 1d. By replacing the phenol with a
hydroxypyridine, the bioavailability, clearance, Cmax, and nor-
malized AUC of 2l were all significantly improved over 2h and
2i.
Niacin has been known to induce FFA reduction in mice and
this effect was niacin receptor dependent.8b It was anticipated
that the lipid effect of niacin treatment was mediated through
GPR109A, and the reduction of FFA in adipocytes eventually
led to TG reduction and HDL-C elevation.3b In mice (p.o.
dosing), 2i was as efficacious in lowering plasma FFA as niacin
(Figure 1) on a dose basis (ED50 ) 9 and 8 mg/kg, respectively).
Furthermore, the in vivo IC50 of 2i was 6.9 µM, whereas the
drug level of niacin at 10 mg/kg p.o. dose in the same FFA
reduction experiment was ∼20 µM. It was estimated that the
in vivo IC50 of niacin in mouse FFA reduction was close to 20
µM. Our PD observation indicated that the in vitro mouse
activity, serum shift, and PK of 2i were sufficient to elicit acute
FFA reduction, which might result in other favorable lipid
effects via GPR109A agonism.
To assess the flushing potential of our compounds, a mouse
model was adopted to measure the extent of vasodilation by
the change in blood perfusion in the mouse ear using laser
Doppler flowmetry.11 In the experiment shown in Figure 2A,
2i failed to induce any vasodilation at the maximum feasible
dose of 100 mg/kg (i.p.). At 15 min post 100 mg/kg dose (i.p.),
the plasma compound level of 2i was 490 µM. The therapeutic
index (TI) could be defined as the minimum drug level that
induces flushing over the IC50 for FFA reduction. Therefore,
the TI of 2i should be over 70 (490 µM/6.9 µM), given that 2i
did not induce flushing even at 490 µM. In contrast, niacin
induced vasodilation at only 3 mpk (i.p.) (Figure 2B), which
corresponded to an 18 µM plasma concentration of niacin at 5
min post-dosing. The time point chosen here corresponded to
the maximum flushing observed at the Tmax for niacin. Thus,
the TI for niacin was virtually 1 (18 µM /20 µM). Compound
2i demonstrated a significantly improved TI with respect to
niacin in mice.
The benchmark compound 2l offered a significant improve-
ment in mouse PK and CYP2C8/2C9 profiles.12 The key step
in the preparation of 2l was the Stille coupling of bromothiazole
5 and 2-trimethylstannyl pyridine 9 (Scheme 2). The desired
product 6 was deprotected and the amino group was converted
to the hydroxyl group via the hydrolysis of the diazonium salt
to accomplish the synthesis of 2l.
In summary, several highly potent biaryl anthranilide deriva-
tives were discovered as agonists of GPR109A with 10–100-
fold more activity than niacin in vitro. We successfully removed
CYP2C8 and 2C9 inhibition, significantly reduced serum shift,
and improved the PK profile of some members of the series

6306 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 25
Letters
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a Reagents and conditions: (a) NaBH4, MeOH, 0 °C, 94%; (b) CBr4,
PPh3, CH2Cl2, 0 °C to rt, 82%; (c) dimethyl malonate, NaH, THF, 0 °C,
83%; (d) LiOH, THF/MeOH/water (3:1:1), rt, 100%; (e) DMF, 170 °C,
99%; (f) MsCl, Et3N, CH2Cl2, then anthranilic acid methyl ester; 0 °C to
rt, 33%; (g) Pd(PPh3)4, CuI, 9, toluene, 120 °C, 79%; (h) NaNO2, H2SO4,
0 °C-73 °C, 13%; (i) SnCl2, EtOH, reflux, 38%; (j) trifluoroacetic
anhydride, DMAP, CH2Cl2, 0 °C to rt, 81%; (k) Pd(PPh3)4, (Me3Sn)2, THF,
80 °C, 50%.
via introduction of five-membered heterocycles in conjunction
with a terminal hydroxypyridine ring. One representative analog
2i showed in vivo FFA reduction efficacy while failing to induce
vasodilation in mice. Our initial studies of the biaryl anthranilide
class demonstrated the possibility of developing niacin receptor
agonists with good efficacy on the proximal biomarker, FFA,
and an improved therapeutic index with respect to niacin-
induced flushing.
Supporting Information Available: Experimental procedures
for compound preparation and characterization data and biological
assay protocols. This material is available free of charge via the
Internet at http://pubs.acs.org.
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JM700942D