AMG 837: A potent, orally bioavailable GPR40 agonist

Article abstract of DOI:10.1016/j.bmcl.2011.10.118

The discovery that certain long chain fatty acids potentiate glucose stimulated insulin secretion through the previously orphan receptor GPR40 sparked interest in GPR40 agonists as potential antidiabetic agents. Optimization of a series of β-substituted p

Full text of DOI:10.1016/j.bmcl.2011.10.118

Bioorganic & Medicinal Chemistry Letters 22 (2012) 1267–1270
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
AMG 837: A potent, orally bioavailable GPR40 agonist
⇑
Jonathan B. Houze , Liusheng Zhu, Ying Sun, Michelle Akerman, Wei Qiu, Alex J. Zhang, Rajiv Sharma,
Michael Schmitt, Yingcai Wang, Jiwen Liu, Jinqian Liu, Julio C. Medina, Jeff D. Reagan, Jian Luo,
George Tonn, Jane Zhang, Jenny Ying-Lin Lu, Michael Chen, Edwin Lopez, Kathy Nguyen, Li Yang,
Liang Tang, Hui Tian, Steven J. Shuttleworth, Daniel C.-H. Lin
Amgen Inc. 1120 Veterans Blvd., South San Francisco, CA 94080, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The discovery that certain long chain fatty acids potentiate glucose stimulated insulin secretion through
the previously orphan receptor GPR40 sparked interest in GPR40 agonists as potential antidiabetic agents.
Optimization of a series of b-substituted phenylpropanoic acids led to the identification of (S)-3-(4-((40-
(trifluoromethyl)biphenyl-3-yl)methoxy)phenyl)hex-4-ynoic acid (AMG 837) as a potent GPR40 agonist
with a superior pharmacokinetic profile and robust glucose-dependent stimulation of insulin secretion
in rodents.
Received 24 August 2011
Accepted 31 October 2011
Available online 6 November 2011
Keywords:
GPR40
FFA1
Ó 2011 Elsevier Ltd. All rights reserved.
Anti-diabetic
GPCR
Agonist
Insulin
Secretagogue
The burden of an epidemic of type 2 diabetes (T2DM) is strain-
ing health care systems both in the United States and worldwide.
The prevalence of diabetes is expected to grow from 171 million
patients worldwide in the year 2000 to 366 million patients (30
million in the United States alone) by 2030.1 However, a more re-
cent report estimates 23.6 million diabetic patients already in the
United States in 2007 with an additional 57 million classified as
pre-diabetics.2 The resulting direct medical costs in the United
States for treating diabetes in 2007 were approximately $116
billion with an additional $58 billion in indirect costs.3
levels would offer a significant benefit to diabetic patients by abat-
ing the risk of hypoglycemia.
The ability of free fatty acids to increase insulin secretion has
been extensively studied both in vitro and in vivo.6–8 The
mechanism behind this effect was clarified with the identification
of GPR40 as an islet expressed receptor for free fatty acids.9
GPR40 (FFA1) is a G q-coupled Class 1 GPCR and is a member
a
of a small family of fatty acid sensing GPCRs that includes
GPR41 (FFA3) and GPR43 (FFA2). GPR40 binds and is activated
by medium to long chain fatty acids (>C6), while the other family
members prefer short chain fatty acids.10 Significantly, the ability
of GPR40 to elicit increased insulin secretion manifests only in
the presence of elevated glucose levels. Therefore a GPR40 agonist
may fulfill the need for an orally bioavailable glucose-dependent
insulin secretagogue.
The potential of GPR40 agonists as antidiabetic agents has not
gone unrecognized, and several groups have published reports
describing potent GPR40 agonists.11,12 In addition to journal publi-
cations, a number of GPR40 agonist series have also been disclosed
in the patent literature.12 Bearing the putative natural ligands of
GPR40 in mind, it is not surprising to find that with few exceptions,
reported GPR40 agonists are generally lipophilic molecules contain-
ing either a carboxylate functionality or a recognizable bioisostere
thereof. A common motif in reported GPR40 agonists is an aryl ring
situated two atoms away from a carboxylate or equivalent group.
Our work began with the identification of a high-throughput
Type 2 diabetes manifests as multiple metabolic defects.4
Preeminent among them are an increased resistance of bodily tis-
sues to the effects of insulin along with a marked decrease in the
insulin secretory response by the pancreas to glucose loads. Target-
ing the latter of these two defects, the sulfonylurea insulin secreta-
gogues inhibit the ATP-sensitive potassium channel that is present
in the b-cells of the pancreatic islet and elicit a sustained elevation
in insulin release.5 This mechanism of augmenting insulin secretion
is insensitive to plasma glucose levels and can lead to overrelease
resulting in hypoglycemia with its attendant symptoms of sweat-
ing, nervousness, dizziness and confusion. While the sulfonylurea
class of antidiabetic agents remain in wide clinical use, an insulin
secretagogue whose activity depends on elevated plasma glucose
⇑
Corresponding author.
E-mail address: jhouze@amgen.com (J.B. Houze).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.10.118

1268
J. B. Houze et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1267–1270
Table 1
screening (HTS) hit falling into this general class that was quickly ex-
panded into a series of b-substituted phenylpropanoates that dis-
played potent agonism on the GPR40 receptor (Table 1).13
b-Substituted phenylpropanoate lead series
R1
O
As shown in Scheme 1, synthetic access to the lead series was a
straightforwardextensionofa literatureprocedure14 involvingaddi-
tion of the desired Grignard reagent to the Meldrum’s acid adduct
with para-methoxybenzyl (PMB) protected p-hydroxybenzalde-
hyde. Hydrolysis and decarboxylation was then carried out in aque-
ous pyridine to obtain the desired carboxylic acids. In order to vary
the benzylic ether portion of the molecule, the head group phenol
was generated by esterifying the carboxylic acid 3 with EDC and eth-
anol followed by selective removal of the PMB ether in refluxing ace-
tic acid. Alkylation of the phenol with a variety of benzylic and non-
benzylic halides could be routinely accomplished in DMF with either
potassium or cesium carbonate as a base. Hydrolysis of the ester un-
der basic conditions then afforded the desired carboxylic acids 5.
OH
β
α
O
O
3a-i
Compound R1
hGPR40 EC50 ( S.D.)a
M)
hGPR40 Emax ( S.D.)b
(%)
(l
3a
3b
3c
–H
1.1 ( 0.09)
3.2 ( 0.1)
0.90 ( 0.7)
94 ( 5)
94 ( 5)
97 ( 9)
3d
3e
3f
0.58 (0.2)
0.12 ( 0.05)
1.2 ( 1)
110 ( 8)
105 ( 5)
82 ( 19)
F
Since, as noted above, GPR40 is a G q-coupled GPCR, compounds
a
were tested for GPR40 activity in a functional assay monitoring cal-
cium flux in CHO cells transiently transfected with GPR40 (details
in Supplementary data). For greater consistency among assay runs,
compound 3g was used as a reference for intrinsic efficacy (defined
as 100%) because the most potent endogenous ligand for GPR40,
docosahexaenoic acid (DHA), is oxidatively unstable.
As shown in Table 1, activity on the GPR40 receptor varies sig-
nificantly with substitution at the b-carbon relative to the carbox-
ylate. While simple alkyl substitution (3b) was deleterious to
GPR40 activity compared to the unsubstituted parent compound,
unsaturated substituents such as alkenes (3e), alkynes (3g), or an
aryl group (3d) improved potency to varying degrees. Among the
unsaturated substituents, branching was preferred remote from
the atom attached to the b-carbon as shown by the greater potency
of compound 3e over 3f.
The alkyne derivative 3g was also of interest due to its good po-
tency, particularly in enantiopure form. The separated enantiomers
of compound 3g showed markedly different activity, with the more
potent enantiomer 3i showing the highest potency in the group. Al-
kyne derivatives also possessed a distinct advantage over alkenes
such as compound 3e in that the GPR40 activity of the alkynes
crossed over fully to the rodent receptors whereas non-alkyne sub-
stituents showed greatly diminished activity on the rodent receptor
(data not shown). Because of the importance of rodent preclinical
models for establishing antidiabetic activity in vivo, further optimi-
zation was focused on the b-alkynyl series.
3g
3h
3i
0.26 ( 0.2)
6.7 ( 2)
100
93 ( 12)
99 ( 5)
0.064 ( 0.02)
a
Mean of at least duplicate runs.
b
% Compared to reference agonist 3g.
Table 2 details exploration of the tail group. Homologating
the benzyl ether (5a) to the phenethyl ether (5b) resulted in
substantial lost potency. Replacement of the methyl ether in
3g with the strongly electron-withdrawing trifluoromethyl group
led to a dramatic loss in both potency and efficacy. In contrast, a
significant increase in potency was obtained by attaching a phe-
nyl group in the meta-position. The preference for meta substitu-
tion was less evident with methoxy substituents (3g vs 5e) than
the phenyls (5h vs 5f). Even in the meta-biphenyl case, however,
shortening the benzyl ether to a diaryl ether (5i) decreased po-
tency. Further improvement in potency could be obtained by
substitution of the terminal arene ring as shown by the trifluo-
romethylated compound 5j.
Because of its high potency, compound 5j was quickly identified
as a compound of interest. Knowing that we preferred a single
enantiomer to interrogate in vivo activity, a non-racemic synthesis
for this compound and others in the series was required. Although
the racemates were separable by chiral HPLC, the process was te-
dious, unpredictable from compound-to-compound, and unsuit-
able for preparing larger amounts of compound in a timely
fashion. A non-racemic synthesis of the key intermediate phenol
(7) not only accelerated new analog synthesis but also enabled
more rapid production of large quantities of compound.
We found it desirable to retain the robust and mild addition of
an alkynyl Grignard reagent to a Meldrum’s acid adduct in order to
form the branched b-center relative to the carboxylic acid. It was
decided to employ a chiral resolution in order to quickly develop
asymmetric access to the desired building block 7. The modified
synthetic sequence is detailed in Scheme 2.
Condensation of p-hydroxybenzaldehyde with Meldrum’s acid
can be carried out in water to obtain a crystalline adduct.15 The addi-
tion of 1-propynylmagnesium bromide to the highly activated Mel-
drum’s acid adduct occurs smoothly even without protection of the
phenol. Hydrolysis and decarboxylation of the Meldrum’s acid moi-
ety can be carried out in aqueous 3-pentanone. The racemic hydro-
xy-acid was then resolved with (1S,2R) -1-amino-2-indanol by
CHO
O
O
a,b
O
c,d
O
O
PMBO
e,f
OH
1
2
R1
OH
R1
O
O
O
HO
O
O
3
4
R1
g,h
OH
O
R2
5
Scheme 1. Reagents and conditions: (a) PMB–Cl, K2CO3, DMF; (b) Meldrum’s acid,
piperidine, acetic acid, toluene; (c) R1MgX, THF; (d) H2O, pyridine, 100 °C; (e) EtOH,
EDC, DMAP; (f) AcOH,
D
; (g) R2X, Cs2CO3, DMF; (h) KOH, EtOH, H2O.

J. B. Houze et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1267–1270
1269
Table 2
Tail group exploration
CHO
a-c
O
O
d-f
O
OH
HO
OH
HO
O
1
6
7
OH
R2
O
F3C
Br
CO2H
5a-j
g-k
+
Compound R1
hGPR40 EC50
( S.D.)a
M)
hGPR40 Emax
B(OH)2
(
l
( S.D.)b (%)
5a
5b
5c
0.62 ( 0.4)
6.2 ( 4)
97 ( 2)
126 ( 6)
97 ( 6)
65 ( 54)
O
F3C
OH
O
0.18 ( 0.1)
27 ( 15)
8 (AMG 837)
F3C
5d
Scheme 2. Non-racemic synthesis of (S)-hexynoate 7 and synthesis of AMG 837.
Reagents and conditions: (a) Meldrum’s acid, H2O, 75 °C, 84%; (b) 1-propynylmag-
nesium bromide, THF; (c) H2O, 3-pentanone, 80 °C 85% over two steps; (d) (1S,2R)-
1-amino-2-indanol, i-PrOH; (e) HCl, H2O, EtOAc, 37% over two steps; (f) MeOH,
H2SO4 (cat.), 95%; (g) Pd/C, i-PrOH, H2O, 90%; (h) LiAlH4, THF, 0 °C, 97%; (i) SOBr2,
CH2Cl2, 92%; (j) 8, Cs2CO3, acetone, 97%; (k) NaOH, EtOH, H2O.
O
5e
0.11 ( 0.05)
1.2 ( 0.6)
104 ( 3)
120 ( 5)
5f
mouse b-cell line (MIN6). As shown in Figure 1, compound 8 is a
highly potent stimulator of insulin secretion in MIN6 cells with an
EC50 comparable to that seen in the aequorin Ca2+-flux assay.
While highly potent on GPR40, compound 8 was inactive on the
closely related GPCRs GPR41 and GPR43. Despite a possible
structural resemblance to some PPAR agonists, compound 8 showed
5g
0.24 ( 0.1)
82 ( 8)
5h
5i
0.058 ( 0.03)
0.36 ( 0.05)
0.025 ( 0.01)
104 ( 4)
106 ( 1)
104 ( 4)
no significant activity in cell-based assays against PPAR-a, -d, and -c.
5j
F3C
a
Mean of at least duplicate runs.
% Compared to reference agonist 3g.
b
repeatedcrystallizationsfrom hot iso-propanol. Afteracid treatment
to break the salt, analysis by chiral HPLC showed 97–98.5% of the de-
sired enantiomer depending on the scale of the resolution. Methyl
ester 7 was then obtained through a Fischer esterification. Notably,
this sequence requires no chromatography save a quick filtration
through silica gel after the esterification step to remove baseline
impurities. The absolute configuration of compound 7 was estab-
lished by derivatization with the Oppolzer camphorsultam auxil-
iary16 and obtaining a crystal structure (see Supplementary data).
From the chiral building block 7, the synthesis of the desired S-enan-
tiomer of 5j was carried out in a straightforward fashion. Improve-
ments to this synthetic sequence to allow preparation of multi-
kilogram amounts of compound 8 as well as an enantioselective syn-
thesis have been reported elsewhere.17,18
Figure 1. Stimulation of insulin secretion in MIN6 Cells by compound 8.
Table 3
Pharmacokinetic properties of compound 8
Property
Mouse
Rat
Beagle Dog
Cynomolgus Monkey
i.v.
Compound 8 displayed the expected two-fold increase in po-
tency on GPR40 (EC50 = 13 [ 7] nM) compared to the racemic com-
pound and its activity crossed over to the rat and mouse forms of
GPR40 (EC50 = 23 and 13 nM, respectively). Because of our interest
in the compound, the intrinsic efficacy of compound 8 was deter-
mined compared to DHA. Compound 8 was thus found to be a partial
agonist on GPR40 with maximal activity 85% of that shown by DHA
under our standard assay conditions.19 In addition to its activity in
the Ca2+-flux assay, compound 8 shows functional activity in a
Dose (mg/kg)
Cl (L/h/kg)
0.8
0.07
8
0.5
0.07
7.2
0.5
0.08
28
0.5
0.06
12.4
0.50
T
½
(h)
Vdss (L/kg)
0.56
0.58
2.1
p.o.
Dose (mg/kg)
%F
5
67
47500
17
0.5
84
6160
1.4
2
0.5
88
7370
2.1
100
33800
7.5
AUC (
l
lM)
gꢀh/L)
Cmax
(

1270
J. B. Houze et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1267–1270
(a)
(b)
(c)
Figure 2. Effect of compound 8 during OGTT in wild type and GPR40 KO mice.
7. Dobbins, R. L.; Chester, M. W.; Daniels, M. B.; McGarry, J. D.; Stein, D. T. Diabetes
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An external panel of 64 receptors also revealed no significant activ-
ity with the exception of weak inhibition (IC50 = 3 M) on the a2
adrenergic receptor. Overall, compound 8 was both highly potent
l
-
9. (a) Itoh, Y.; Kawamata, Y.; Harada, M.; Kobayashi, M.; Fujii, R.; Fukusumi, S.;
Ogi, K.; Hosoya, M.; Tanaka, Y.; Uejima, H.; Tanaka, H.; Maruyama, M.; Satoh,
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T.; Hinuma, S.; Fujisawa, Y.; Fujino, M. Nature 2003, 422, 173; (b) Briscoe, C. P.;
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Jr.; Shabon, U.; Spinage, L. D.; Strum, J. C.; Szekeres, P. G.; Tan, K. B.; Way, J. M.;
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and selective in vitro.
In addition to its favorable profile in vitro, compound 8 distin-
guished itself by displaying an excellent pharmacokinetic profile
in multiple species. As shown in Table 3, compound 8 combines
low clearance, long half-life, and high oral bioavailability in four
preclinical species.
In order to confirm that the potential antidiabetic activity of
compound 8 was mediated by GPR40, an oral glucose tolerance
test (OGTT) was carried out in wild-type and GPR40 KO mice.
The DPP-4 inhibitor sitagliptin was used at a maximally efficacious
dose as a positive control.20 Compounds were dosed orally 60 min
prior to the oral glucose challenge. As shown in Figure 2, com-
pound 8 substantially blunted plasma glucose excursion compared
to both vehicle and positive control in wild-type animals consis-
tent with its activity as an insulin secretagogue as shown in
MIN6 cells (Fig. 2a). The total glucose AUC was also reduced in a
statistically significant manner (Fig. 2c). In contrast, no effect in
the OGTT was seen in the GPR40 KO animals after dosing with
10. Brown, A. J.; Jupe, S.; Briscoe, C. P. DNA Cell Biol. 2005, 24, 54.
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compound
8 where the positive control retained activity
(Fig. 2b). The complete absence of a response in the GPR40 KO ani-
mals establishes that the effects of compound 8 are GPR40 medi-
ated. The behavior of compound 8 in this GTT study is consistent
with the hypothesis that selective GPR40 agonists could serve as
glucose-dependent insulin secretagogues.
In summary, through optimization of a lead series of simple ben-
zyloxy-substituted phenylpropanoic acids, we identified compound
8 as a highly potent agonist of GPR40. Due to its combination of high
in vitro potency and selectivity, favorable pharmacokinetic profile,
and robust GPR40-mediated in vivo antidiabetic activity, compound
8 (AMG 837) was selected for clinical evaluation.
12. For reviews, see: (a) Medina, J. C.; Houze, J. B. Annu. Rep. Med. Chem. 2008, 43,
75; (b) Bharate, S. B.; Nemmani, K. V. S.; Vishwakarma, R. A. Expert Opin. Ther.
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13. Houze, J.; Qiu, W.; Zhang, A.; Sharma, R.; Zhu, L.; Sun, Y.; Akerman, M.; Schmitt,
M.; Wang, Y.; Liu, J.; Liu, J.; Medina, J.; Reagan, J.; Luo, J.; Tonn, G.; Zhang, J.; Lu,
J.; Chen, M.; Lopez, E.; Nguyen, K.; Li, Y.; Tang, L.; Tian, H.; Shuttleworth, S.; Lin,
D. Abstracts of Papers, 234th ACS National Meeting, Boston, MA, United States,
August 19–23, 2007, MEDI-251.
Supplementary data
14. DeWolf, W. E.; Chambers, P. A.; Southan, C.; Saunders, D.; Kruse, L. I.
Biochemistry 1989, 28, 3833.
15. Bigi, F.; Carloni, S.; Ferrari, L.; Maggi, R.; Mazzacani, A.; Sartori, G. Tetrahedron
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Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2011.10.118.
16. Oppolzer, W. Tetrahedron 1987, 43, 1969.
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