Pyrido pyrimidinones as selective agonists of the high affinity niacin receptor GPR109A: Optimization of in vitro activity

Article abstract of DOI:10.1016/j.bmcl.2010.07.108

Pyrido pyrimidinones are selective agonists of the human high affinity niacin receptor GPR109A (HM74A). They show no activity on the highly homologous low affinity receptor GPR109B (HM74). Starting from a high throughput screening hit the in vitro activity of the pyrido pyrimidinones was significantly improved providing lead compounds suitable for further optimization.

Full text of DOI:10.1016/j.bmcl.2010.07.108

Bioorganic & Medicinal Chemistry Letters 20 (2010) 5426–5430
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Pyrido pyrimidinones as selective agonists of the high affinity niacin receptor
GPR109A: Optimization of in vitro activity
a
a
Jens-Uwe Peters a, Holger Kühne a, Henrietta Dehmlow a, Uwe Grether a, , Aurelia Conte , Dominik Hainzl ,
Cornelia Hertel a, Nicole A. Kratochwil a, Michael Otteneder a, Robert Narquizian a,
Constantinos G. Panousis b, Fabienne Ricklin a, Stephan Röver a
*
a Pharma Research, F. Hoffmann-La Roche Ltd, 4070 Basel, Switzerland
b Pharma Research, F. Hoffmann-La Roche Ltd, Nutley, NJ 07110, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Pyrido pyrimidinones are selective agonists of the human high affinity niacin receptor GPR109A
(HM74A). They show no activity on the highly homologous low affinity receptor GPR109B (HM74). Start-
ing from a high throughput screening hit the in vitro activity of the pyrido pyrimidinones was signifi-
cantly improved providing lead compounds suitable for further optimization.
Received 17 June 2010
Revised 23 July 2010
Accepted 25 July 2010
Available online 29 July 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Flushing
GPR109A
GPR109B
GPCR
Lead identification
Lipolysis
Niacin
Pyrido pyrimidinone
Niacin, a vitamin of the B complex, has been used for almost 50
years as an anti-dyslipidemic drug with a favorable profile for all
lipoprotein classes. In particular, niacin is the most potent agent
to raise high density lipoprotein cholesterol (HDL-c).1–3 Numerous
clinical studies have shown the beneficial effects of niacin, namely
a reduction of coronary artery disease and overall mortality.4,5
However, extensive use of niacin is limited due to transient skin
vasodilatation (flushing) affecting most of the patients.6 Extended
release formulations of niacin (e.g., NiaspanÒ) show a reduction
in flushing events, but are not able to overcome this side effect
completely.4,7 In addition, doses of extended release niacin formu-
lations are limited due to hepatotoxicity caused by niacin metabo-
lites.8,9 It has been proposed that niacin’s main mode of action is
inhibiting lipolysis in the adipose tissue.2 As a consequence, free
fatty acid (FFA) levels in plasma and liver are lowered leading to
a decreased production of very low density lipoprotein cholesterol
(VLDL-c). This results in a reduction of total plasma cholesterol
(TC), triglyceride (TG), and LDL-c levels. Due to the lower number
of TG rich lipoprotein particles in plasma, fewer modifications of
the HDL-c particles via the cholesteryl ester transfer protein (CETP)
occur, which leads to a decrease in HDL-c catabolism.10,11 A niacin-
mediated direct inhibition of lipoprotein A-I HDL-c (LpAI-HDL-c)
particle uptake by the liver, which would contribute to the overall
HDL-c raising properties of niacin, has also been proposed.12 In
addition, the anti-dyslipidemic effects of niacin are discussed in
the context of its diacylglycerol acyltransferase 2 (DGAT2) inhibi-
tory effects.3
In 2003, three independent groups identified GPR109A (HM74A)
and GPR109B (HM74), two GPCRs, as the receptors for niacin.13–15
GPR109A, which is present in all species, is a high affinity receptor
for niacin.14,16 GPR109B, which is only present in human and chim-
panzee, is a low affinity receptor for niacin.17,18 The lack of this
ortholog in rodents suggests that GPR109A is sufficient for the anti-
lipolytic activity of niacin in vivo.14,19 However, deletion of the
GPR109A-receptor in mice showed that this receptor can be respon-
sible for both effects of niacin: lipid lowering as well as prostaglan-
din-mediated transient skin vasodilation.20 Several approaches to
dissect the desired dyslipidemic effects from the undesired flushing
effect are under discussion: (i) avoid high cmax values (e.g., like with
immediate release niacin)21,22 and strive for low cmax/ctrough ratios
(e.g., slow release niacin)22 assuming that cmax drives the flushing;
(ii) combine niacin or a novel GPR109A agonist with aspirin or a
prostaglandin D2 inhibitor;23 (iii) use positive allosteric agonists;24
(iv) develop partial GPR109A agonists.25 Supported by the compar-
ison of immediate release niacin versus sustained release niacin, we
* Corresponding author. Tel.: +41 616885446; fax: +41 616889748.
E-mail address: uwe.grether@roche.com (U. Grether).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.07.108

J.-U. Peters et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5426–5430
5427
hypothesized that a pharmacokinetic profile which is characterized
by a low cmax/ctrough ratio, a very low volume of distribution and a
very low clearance is essential to achieve a separation between de-
HTS hit 1 already has interesting binding affinities to the human
and rat receptor as well as good functional activity (Table 1).
Unfortunately, clearance determined in vitro from rat liver
microsome incubations was high. This translated also into a high
clearance in vivo which was accompanied by a short plasma
half-life in rat after iv dosing leading overall to a high cmax/ctrough
value. Therefore, further in vivo profiling was prohibited and an
in vitro optimization program was initiated. As expected from
the proposed binding mode derived from the mutational studies,
the pyrido pyrimidinone scaffold is essential for activity. Replace-
ment of any of the nitrogen atoms by a carbon atom or alkylation
of the pyrimidinone-NH rendered the scaffold significantly less ac-
tive or even inactive (data not shown). Moreover, the trifluoro-
methyl group could not be replaced with small alkyl, acyl, aryl, alk-
oxy, and alkylamino groups without substantial loss of activity.
Based on the modeling hypothesis, the possibility to extend this
exit vector was probed and substituents containing a phenyl group
attached to a simple alkyl-chain linker were identified as suitable
replacements for the trifluoro-methyl group (Table 2).
A linker length of 4 and 5 atoms was found to be optimal (5 and
6) compared to the only weakly active compounds with longer
linkers (7 and 8) or the inactive compounds with shorter linker
chains (2–4). In a next step incorporation of hetero-atoms in the
linker was explored (Table 3). An amide linker as in 14 and differ-
ent ether linkers improved affinity compared to 5 and 6 with the
most interesting compounds being 10 and 13.
To further improve the activity of compounds 10 and 13 the
influence of substitution at the phenyl ring was investigated with
small substituents. Whereas the introduction of methoxy-groups
was not beneficial, chlorine or fluorine substitution in ortho or
meta position led to compounds with very high affinity to the
GPR109A-receptor such as 13-o-Cl and 10-m-Cl (Tables 4 and 5).
These compounds also exhibited very good functional activity
at the human and rat receptor. Unfortunately, their in vitro micro-
somal clearance was not improved compared to 1 (Table 6). There-
fore, the slightly less potent but metabolically more stable
compound 10-p-F was selected for in vivo PK profiling. Surpris-
ingly, the half-life after iv dosing was even shorter than that of 1,
despite lower clearance in microsomes. Partly, this can be ex-
sired and side effect. Immediate release niacin (high cmax/ctrough
)
causes flushing in >90% of all patients whereas sustained release also
called ‘no flush’ niacin (low cmax/ctrough) avoids flushing but leads to
severe liver toxicity.26 Since this liver toxicity is linked to a niacin
specific metabolite we were confident to overcome this issue with
a structurally different GPR109A agonist. To probe the PK hypothesis
a chemistry program based on the high throughput screening hit 1
was initiated. The optimization of the in vitro activity of these pyrido
pyrimidinones on GPR109A will be described in this Letter.
Receptor-based modeling driven mutational studies supported
the medicinal chemistry efforts. Niacin and pyrido pyrimidinone
1 were docked into a 3D receptor pharmacophore model of the
GPR109A transmembrane binding pocket (Fig. 1). The binding
mode hypothesis of niacin is in agreement with the work of Tunaru
et al.17 and in-house site-directed mutagenesis studies. It proposes
an interaction of the carboxyl group of nicotinic acid with R1113.36
at TM3 and a hydrogen bond between the nitrogen of the pyridine
ring and the hydroxyl group of the S17845.51 at EC2. The pyridine
ring is embedded between TM2/EC1 and TM7 (Y2847.43). The addi-
tional critical determinants, F2767.35 and amino acids in the EC1
(N86, W91), of the niacin binding pocket are in close proximity
to the hypothesized binding mode of niacin, but are not shown
due to reasons of clarity. In addition, a possible binding mode for
pyrido pyrimidinone 1 is presented. The nitrogens of the pyridine
and pyrimidinone ring mimic the carboxyl group of the nicotinic
acid interacting with R1113.36 at TM3 and the carbonyl group of
the pyrimidinone forms a hydrogen bond with the hydroxyl group
of the S17845.51 at EC2. The trifluoro substituent points towards the
binding pocket arranged by TM5 and TM6 demonstrates the possi-
bility to extend this exit vector.
Table 1
In vitro pharmacology and PK profile of HTS hit 1
O
NH
CF3
N
N
1
a,b
IC50 (hGPR109A)
1.3
>50
lM
lM
a,b
IC50 (hGPR109B)
c
EC50 (GTP
c
S, hGPR109A)
1.7
0.4
0.06
4.9
58
84
8800
0.4
lM
a,b
IC50 (rGPR109A)
l
M
c
EC50 (GTP
c
S, rGPR109A)
lM
d
CLint (h,
ll/min/mg)
e
CLint (r,
ll/min/mg)
CLf (ml/min/kg)
Figure 1. 3D receptor pharmacophore model of the GPR109A transmembrane
binding pocket. The binding pocket is docked with niacin (green) and pyrido
pyrimidinone 1 (magenta). For illustration purposes, the two compounds are not
completely overlaid rather shown at parallel positions. Important residues are
labeled in Ballesteros–Weinstein nomenclature in addition to the one letter amino
acid code. The amino acids of the GPR109A transmembrane binding pocket are
shown as spheres, whereas the size corresponds to the size of the side chain of the
amino acids. The pharmacophoric spheres are colored according to their pharma-
cophoric properties. Hydrophobic amino acids (F, P, M, A, L, I, G, V, and W) gray, H-
donor/acceptor (Y, T, S, H, C, N, and Q) magenta, H-bond donors with a positive
charge (R) yellow/blue. Possible H-bond interactions are presented as dotted lines.
C atoms of niacin and pyrido pyrimidinone 1 are displayed in white, oxygen in red,
nitrogen in blue, and fluorine in green.
f
cmax (ng/ml)
f
Vss (l/kg)
t1/2 (h)
f
0.5
a
b
c
d
e
f
Inhibition of radioligand binding.
The variability of the IC50 determinations was on average 10%.
All GTP S measurements were performed at least in duplicates.
From incubations with human liver microsomes; mg = mg of protein.
Rat liver microsomes.
c
The HTS hit 1 was administered to Wistar rats for intravenous bolus adminis-
tration. Rats (N = 2 per dose) were dosed intravenously with 5 mg/kg and blood
samples were taken up to 24 h by jugular vein cannulation.

5428
J.-U. Peters et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5426–5430
Table 5
Table 2
SAR exploration of aromatic ring substituents in 10 (inhibition of radioligand binding,
M)
Replacement of the CF3 group of 1
l
O
N
O
NH
NH
N
R
O
N
N
R
a
Compounds
R
IC50 (lM)
10
2
3
4
5
6
7
8
–(CH2)Ph
–(CH2)2Ph
–(CH2)3Ph
–(CH2)4Ph
–(CH2)5Ph
–(CH2)6Ph
–(CH2)7Ph
>50
>50
>50
4.4
5.9
19
10 (R = H): 0.67
R=
F
Cl
Me
OMe
ortho
meta
para
0.22
0.23
0.63
0.60
0.05
1.2
0.44
0.41
4.3
1.7
1.5
4.4
48
a
Inhibition of radioligand binding.
Table 6
In vitro pharmacology and PK profiles of compounds 13-o-Cl, 10-m-Cl, and 10-p-F
Table 3
Exploration of linker chain analogs of 5 and 6
O
O
Cl
NH
NH
O
N
N
O
N
N
O
R
13-o-Cl
a
Compound
R=
IC50 (lM)
O
N
9
10
11
12
13
0.84
0.67
>50
O
NH
Cl
O
N
O
10-m-Cl
0.37
0.13
O
O
O
N
O
H
N
NH
14
0.92
O
N
O
a
F
Inhibition of radioligand binding.
10-p-F
13-o-Cl
0.015
33
0.05
1.4
0.19
201
165
n.d.
n.d.
n.d.
n.d.
10-m-Cl
10-p-F
Table 4
SAR exploration of aromatic ring substituents in 13 (inhibition of radioligand binding,
M)
a
IC50 (hGPR109A,
l
M)
0.05
n.d.
0.34
0.64
0.14
24
0.63
a
IC50 (hGPR109B)
l
M
>50
2.5
2.7
1.6
11
lM
l
EC50 (GTP
c
S, hGPR109A,
IC50 (rGPR109A, M)
EC50 (GTP S, rGPR109A,
l
M)
a
O
l
c
lM)
NH
b
CLint (h,
ll/min/mg)
R
c
CLint (r,
ll/min/mg)
60
18
30
9700
0.07
0.05
O
N
O
N
CLd (ml/min/kg)
n.d.
n.d.
n.d.
n.d.
cmax (ng/ml)d
13
d
Vss (l/kg)
13 (R = H): 0.13
d
t1/2 (h)
R=
F
Cl
Me
OMe
n.d., not determined.
a
Inhibition of radioligand binding.
From incubations with human liver microsomes; mg = mg of protein.
Rat liver microsomes.
ortho
meta
para
0.25
0.37
1.1
0.015
0.033
0.23
0.45
0.86
4.7
n.d.
n.d.
6.3
b
c
d
The compounds were administered to Wistar rats for intravenous bolus
administration. Rats (N = 2 per dose) were dosed intravenously with 5 mg/kg and
n.d., not determined.
blood samples were taken up to 24 h by jugular vein cannulation.
plained by a fivefold lower volume of distribution of compound 10-
p-F compared to compound 1. Another reason however is a mis-
match of microsomal and in vivo clearance that was later found
to originate from efficient extra-hepatic metabolism; the elucida-
tion of this elimination mechanism, and the further optimization
of metabolic stability, will be the subject of a later publication.
Representative syntheses of pyrido pyrimidinones are outlined
in Schemes 1–4 and follow two general routes. On one hand, side
chains can be introduced by N-acylation of 2-amino-nicotinonitrile
O
N
N
O
N
a
b
NH
CF3
N
N
CF3
N
NH2
N
H
15
16
1
Scheme 1. Reagents and conditions: (a) (CF3CO)2O, pyridine, THF, 0 °C to rt o.n.,
98%; (b) NaOH, H2O2, EtOH/H2O, 4 h reflux then rt o.n., 76%.27

J.-U. Peters et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5426–5430
5429
In summary, a novel class of agonists for the human GPCR,
GPR109A (HM74A), the pyrido pyrimidinones has been discovered
and optimized. These molecules show no activity on the highly
homologous low affinity receptor GPR109B (HM74). Based on the
high throughput screening hit 1 and supported by receptor-based
modeling the key pharmacophore moieties of the pyrido pyrimid-
inones have been identified and a first comprehensive SAR study of
such molecules was established making use of human GPR109A
N
O
HOOC
a, b
N
N
H
17
18
O
c
NH
binding and GTPcS assays. Elongation at the 2-position of the pyr-
N
N
ido pyrimidinone led to molecules with significantly improved
in vitro activity. Although selected compounds of this class, for
example, 10-p-F, show an improved microsomal clearance com-
pared to the HTS hit compound 1, this is not mirrored by clearance
and half-life in rat pharmacokinetic studies. Progress made to ad-
dress this issue in order to come up with GPR109A agonists which
avoid high cmax values, have low cmax/ctrough ratios and therefore
might be able to dissect desired dyslipidemic effects from the
undesired flushing effect will be reported in due course.
5
Scheme 2. Representative procedure for the preparation of 2-substituted pyrido
pyrimidinones from carboxylic acids. Reagents and conditions: (a) (COCl)2, DMF,
CH2Cl2, 2 h, rt; (b) add to 15, pyridine, CH2Cl2, rt o.n., 75%; (c) NaOH, H2O2, EtOH/
H2O, 3 h reflux, 34%.28
Cl
Cl
a
Acknowledgments
HO
HO
O
The authors gratefully acknowledge contributions by Caroline
Brugger, Marie-Paule Imhoff, Stephane Kritter, Flore Reggiani,
Ernst Schaffter, and Silja Weber for chemical syntheses, Athanasios
Denelavas, Régine Gerard, Gabriele Raphael, and Laura Schoepflin
for in vitro testing and Dr. Manfred Kansy for investigations on
physicochemical properties.
19
20
O
N
O
N
b
Cl
NH
Cl
NH
O
N
N
O
21
13-o-Cl
References and notes
Scheme 3. Representative procedure for the preparation of 13 from 21.29 Reagents
and conditions: (a) Cl(CH2)3OH, K2CO3, DMF, 60 °C o.n., 76%; (b) 20, KOtBu, DMSO,
120 °C o.n., 22%.28,29
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