Discovery and optimization of potent GPR40 full agonists containing tricyclic spirocycles

Article abstract of DOI:10.1021/ml300427u

GPR40 (FFAR1 or FFA1) is a target of high interest being pursued to treat type II diabetes due to its unique mechanism leading to little risk of hypoglycemia. We recently reported the discovery of AM-1638 (2), a potent full agonist of GPR40. In this repor

Full text of DOI:10.1021/ml300427u

Letter
pubs.acs.org/acsmedchemlett
Discovery and Optimization of Potent GPR40 Full Agonists
Containing Tricyclic Spirocycles
Yingcai Wang,* Jiwen (Jim) Liu, Paul J. Dransfield, Liusheng Zhu, Zhongyu Wang, Xiaohui Du,
Xianyun Jiao, Yongli Su, An-rong Li, Sean P. Brown, Annie Kasparian, Marc Vimolratana, Ming Yu,
Vatee Pattaropong, Jonathan B. Houze, Gayathri Swaminath, Thanhvien Tran, Khanh Nguyen, Qi Guo,
Jane Zhang, Run Zhuang, Frank Li, Lynn Miao, Michael D. Bartberger, Tiffany L. Correll, David Chow,
Simon Wong, Jian Luo, Daniel C.-H. Lin, and Julio C. Medina
Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc., 1120 Veterans Boulevard, South San
Francisco, California 94080, United States and One Amgen Center Drive, Thousand Oaks, California 91320, United States
S
* Supporting Information
ABSTRACT: GPR40 (FFAR1 or FFA1) is a target of high interest
being pursued to treat type II diabetes due to its unique mechanism
leading to little risk of hypoglycemia. We recently reported the
discovery of AM-1638 (2), a potent full agonist of GPR40. In this
report, we present the discovery of GPR40 full agonists containing
conformationally constrained tricyclic spirocycles and their structure−
activity relationships leading to more potent agonists such as AM-5262
(26) with improved rat PK profile and general selectivity profile. AM-
5262 enhanced glucose stimulated insulin secretion (mouse and
human islets) and improved glucose homeostasis in vivo (OGTT in
HF/STZ mice) when compared to AM-1638.
KEYWORDS: GPR40, full agonist, spirocycles, tricyclic, AM-5262, AM-1638, AMG 837, FFAR1, FFA1
ype II diabetic patients lose their ability to maintain
Tglucose homeostasis due to defects in both insulin
secretion and action.1 GPR40 (FFAR1 or FFA1) is a G-
protein-coupled receptor, primarily expressed in pancreatic islet
β-cells and intestinal enteroendocrine cells.2 When activated by
medium to long chain fatty acids, GPR40 elicits increased
insulin secretion from islet β-cells only in the presence of
elevated glucose levels.3 This unique mechanism to treat type II
diabetes potentially mitigates the risk of hypoglycemia seen
with standard insulin secretagogues and has triggered significant
efforts at identifying therapeutic agents utilizing this target.4−21
We previously described the discovery of a GPR40 partial
agonist AMG 837 (1, Figure 1)16 and a GPR40 full agonist
AM-1638 (2).21 AM-1638 showed greater antidiabetic efficacy
in several rodent models21,22 and provided compelling evidence
that GPR40 full agonists can afford access to a powerful
mechanism for maintaining glycemic control and great
potential for the treatment of type II diabetic patients.
In this letter, we describe further optimization beyond AM-
1638. We took on an approach to add conformational
constraints, especially at the flexible phenylpropanoic acid
region (subsequently referred to as the “head group”, Figure 1).
Our efforts to define conformational constraints that
maintain full agonist activity are shown in Table 1. Compared
to phenylpropanoic acid (3), constraining the phenyl with a
fused 5-membered ring (4) showed a modest improvement in
potency. To further constrain the carboxylic acid, we explored
fusing a cyclopropane to the cyclopentane ring of the 2,3-
dihydro-1H-indene (4). Incorporation of cyclopropane through
the fused connection (examples 5−8) proved to be detrimental
to potency, although 8 still retained full agonism. However,
switching to a spiro-cyclopropane attached to the dihydroin-
dene (examples 9−12) resulted in increased potency (12 vs 4),
while maintaining full agonism on GPR40. Note that only one
of the four possible stereoisomers maintains both high potency
and full efficacy on the target. To probe whether the tricyclic
constraint was necessary, we eliminated the cyclopentane ring
and made 2-phenylcyclopropanecarboxylic acids 13 and 14.
This change resulted in a 10-fold loss in potency and reduced
efficacy.
Received: November 29, 2012
Accepted: May 7, 2013
Figure 1. GPR40 partial agonist AMG 837 and full agonist AM-1638.
© XXXX American Chemical Society
A
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Table 1. Identification of Spirocyclic Head Groups
Scheme 1
a
Reagents and conditions: (a) TBDPSCl, imidazole, DMF, 60 °C,
100%; (b) Ph3PCH3Br, t-BuOK, THF, 99%; (c) Rh2(OAc)4,
N2CHCOOEt, CH2Cl2, 45 °C, 80%; (d) TBAF, THF, 0 °C, 62%
(total); chiral separation of four isomers: Chiracel AD-H column, 5%
IPA/hexane.
Table 2. Optimization of Spirocyclic Ring Sizes
a
b
Mean of at least two runs. % maximal efficacy compared to 2.
a
b
Mean of at least two runs. % maximal efficacy compared to 2.
Absolute configurations were defined based on comparison of
experimental and calculated vibrational circular dichroism
(VCD)23 spectra and optical rotations.24 The configuration of
head group 19 (in compound 11, Table 1) was further verified
by X-ray analysis of its brominated analogue.25
We then turned our attention to optimize the sizes of the
spirocyclic rings (Table 2). Compared to the spiro[2,4]heptane
in 12, the spiro[2,5]octane in 22 showed equal potency and
efficacy. Other variations on ring sizes (23−25) showed
decreased potencies and thus indicated less optimal conforma-
tional restrictions than 12 and 22; however, they were still
equal to or better than the flexible phenylpropanoic acid 3.
A large scale synthetic route to prepare head groups shown in
examples 9−12 was developed (Scheme 1). Commercially
available 6-hydroxy-1-indanone (250 g) was protected with tert-
butyldiphenylsilyl group, followed by a Wittig reaction to
deliver the terminal olefin 16 in quantitative yields for both
steps. Rhodium acetate catalyzed cyclopropanation with ethyl
diazoacetate resulted in 17 in 80% yield. Deprotection followed
by chiral separation delivered the head groups 18−21.
The relative configurations of the head groups shown in
compounds 5−12 were assigned based on NMR studies.
B
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ACS Medicinal Chemistry Letters
Letter
Table 3. Combination of Best Head and Tail Groups
Table 5. Improvement in Pharmacokinetic Properties
a
a
a
b
compd
species
rat
Cl (L/h/kg) Vdss (L/kg) iv t1/2 (h) % F
2
0.91
0.81
0.25
0.84
0.17
0.11
1.1
2.0
0.7
1.4
0.8
0.4
1.8
2.1
4.2
2.2
4.1
3.7
15
71
28
69
61
44
c
cyno
26
30
rat
c
cyno
rat
c
cyno
a
b
c
iv dose at 0.5 mg/kg. Oral dose at 2 mg/kg. Cynomolgus monkey.
Figure 2. Binding of AM-5262 was examined in cross-interaction
experiments with [3H] AMG 837 (A) and [3H] AM-1638 (B). Data
are expressed as cpm specific binding and shown as means SEM of
2−3 independent experiments. The curves are fitted to an allosteric
ternary complex model.
a
b
Mean of at least two runs. % maximal efficacy compared to 2.
Scheme 2
a
Reagents and conditions: (a) [Ru(p-cymene)Cl2]2, 2,6-Bis[(4S)-
(−)-isopropyl-2-oxazolin-2-yl]pyridine, N2CHCO2Et, THF, 60 °C,
94%, 90% ee; (b) Pd/C, H2, EtOAc, 95%; (c) Cs2CO3, DMSO, 16 h;
then added 2 N aqueous LiOH and MeOH, 50 °C, 15 h, 72%.
Table 4. Binding Activity Screen against 101 Receptors
number of receptors that have
Figure 3. Characterization of AM-5262 activity in isolated primary
cells. Stimulation of (A) GLP-1 and (B) GIP secretion by AM-1638
and AM-5262 from rat fetal intestinal cells. Potentiation of glucose-
dependent insulin secretion from (C) mouse and (D) human islets in
response to indicated treatments.
a
a
a
compd
>90% POC
>80% POC
>70% POC
2
4
1
2
9
3
6
12
6
26
30
6
a
Percent inhibition of control values or control specific binding.
found to be most effective to deliver the 18 precursor 32 in
94% yield with 90% ee. Coupling the head group 18 with tail
group 33 was accomplished at room temperature with Cs2CO3
in DMSO, followed by hydrolysis with aqueous LiOH and
MeOH to deliver 26 in one pot.
Highly conformationally constrained molecules, like 26 and
30, were expected to improve off-target selectivity.27 Both 26
and 30 showed better selectivity than 2 against a broad panel of
101 GPCRs, ion channels, transporters, and enzymes at 10 μM
(Table 4, additional detail in Supporting Information).
Reduction of the cyclopentene in the tail region of 12
resulted in potency improvement for 26, but not its
diastereoisomer 27, although both have full efficacy (Table
3). The spiro[2,5]octanes (28−30) again showed similar
potency as spiro[2,4]heptane (26).
The preparation of these spirocyclic GPR40 full agonists is
exemplified by the synthesis of 26 (Scheme 2). Asymmetric
approaches to 18 were explored, and the chiral ruthenium
bis(oxazolinyl) pyridine catalyst reported by Nishiyama26 was
C
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was 2−5-fold greater than AM-1638 (Figure 3A,B). AM-5262
potentiated glucose stimulated insulin secretion from both
mouse (Figure 3C) and human islets (Figure 3D), and the
activity was greater than that of exendin-4 in human islets.
When compared for their ability to improve glycemic control
in HF/STZ type II diabetic mice,22 AM-5262 showed similar
efficacy at 30 mg/kg dose compared to AM-1638 at 60 mg/kg
during an oral glucose tolerance test (OGTT, Figure 4A). AM-
1638 displays maximal efficacy at 60 mg/kg in this model.
Glucose AUC improved ∼48% in response to 30 mg/kg AM-
5262, and this was associated with an increase in insulin
secretion (Figure 4B). Total plasma levels of drugs were
measured one hour post-dose (Figure 4C). Total drug plasma
levels were 6−7-fold lower for AM-5262 at 30 mg/kg compared
to AM-1638 at 60 mg/kg, suggesting that AM-5262 displays
greater potency in vivo.
In conclusion, we have described the discovery and SAR of
potent GPR40 full agonists with highly conformationally
constrained tricyclic head groups. These compounds demon-
strated improved rat PK and off-target selectivity profiles
compared to their unconstrained parent compounds. AM-5262
(26) binds to the same ligand site on GPR40 as AM-1638 and
has enhanced glucose stimulated insulin secretion (mouse and
human islets) and improved glucose homeostasis in vivo
(OGTT in HF/STZ mice).
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, analytical data, and receptor screen-
ing data. This material is available free of charge via the Internet
at http://pubs.acs.org.
Figure 4. AM-5262 improves glucose metabolism in high-fat fed/STZ
treated mice. (A) Glucose and (B) insulin levels during an OGTT in
response to treatments indicated in the figure legends. Compounds
were dosed orally at −60 min, and oral glucose was administered at 0
min. (C) Total (bound + free) drug levels in the plasma 1 h post-drug
dose during the OGTT.
AUTHOR INFORMATION
Corresponding Author
*(Y.W.) E-mail: yingcaiw@amgen.com.
Notes
■
The authors declare no competing financial interest.
REFERENCES
■
Compound 2 showed greater than 70% inhibition compared to
controls for the adenosine A1 receptor, thyrotropin releasing
hormone TRH1 receptor, the norepinephrine transporter, the
cholecystokinin CCK2 receptor, the histamine H4 receptor, the
dopamine D1 receptor, and the kappa opioid receptor; while 26
and 30 displayed less than 70% inhibition against these
receptors.
Compound 2 has medium clearance in both rats (Cl = 0.91
L/h/kg) and cynomolgus monkeys (cyno, Cl = 0.81 L/h/kg).
Table 5 showed that 26 improved clearance in rat (0.25 L/h/
kg) and that 30 improved clearance by 5−7-fold in both rat and
cyno.
Binding data obtained from reciprocal competition experi-
ments demonstrated that similarly to AM-1638 (2), AM-5262
(26) exhibits positive cooperativity and occupies a different
binding site from AMG 837 (Figure 2).28 Conversely,
experiments with radiolabeled AM-1638 clearly showed that
AM-5262 binds at the same site as AM-1638, further providing
evidence of allosteric behavior with AMG 837.
GPR40 full agonists stimulate incretin and insulin secretion
in vitro and in vivo.22 The activity of AM-5262 was compared
head-to-head with AM-1638 in isolated primary cells from
rodents and humans. AM-5262 stimulated GLP-1 and GIP
secretion from rat intestinal cells, and the potency of AM-5262
(1) Defronzo, R. A. From the triumvirate to the ominous octet: A
new paradigm for the treatment of type 2 diabetes. Diabetes 2009, 58,
773−795.
(2) 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, R.; Okubo, S.; Kizawa, H.; Komatsu, H.;
Matsumura, F.; Noguchi, Y.; Shinohara, T.; Hinuma, S.; Fujisawa, Y.;
Fujino, M. Free fatty acids regulate insulin secretion from pancreatic β
cells through GPR40. Nature 2003, 422, 173−176.
(3) Stoddart, L. A.; Smith, N. J.; Milligan, G. International union of
pharmacology. LXXI. Free fatty acid receptors FFA1, -2, and -3:
pharmacology and pathophysiological functions. Pharmacol. Rev. 2008,
60, 405−417.
(4) For a review, see: Medina, J. C.; Houze, J. B. GPR40 (FFAR1)
modulators. Annu. Rep. Med. Chem. 2008, 43, 75−85.
(5) For a review on patents, see: Bharate, S. B.; Nemmani, K. V.;
Vishwakarma, R. A. Progress in the discovery and development of
small-molecule modulators of G-protein-coupled receptor 40
(GPR40/FFA1/FFAR1): An emerging target for type 2 diabetes.
Expert Opin. Ther. Pat. 2009, 19, 237−264.
(6) Garrido, D. M.; Corbett, D. F.; Dwornik, K. A.; Goetz, A. S.;
Littleton, T. R.; McKeown, S. C.; Mills, W. Y.; Smalley, T. L.; Briscoe,
C. P.; Peat, A. J. Synthesis and activity of small molecule GPR40
agonists. Bioorg. Med. Chem. Lett. 2006, 16, 1840−1845.
(7) McKeown, S. C.; Corbett, D. F.; Goetz, A. S.; Littleton, T. R.;
Bigham, E.; Briscoe, C. P.; Peat, A. J.; Watson, S. P.; Hickey, D. M. B.
D
dx.doi.org/10.1021/ml300427u | ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX

ACS Medicinal Chemistry Letters
Letter
Solid phase synthesis and SAR of small molecule agonists for the
GPR40 receptor. Bioorg. Med. Chem. Lett. 2007, 17, 1584−1589.
(8) Song, F.; Lu, S.; Gunnet, J.; Xu, J. Z.; Wines, P.; Proost, J.; Liang,
Y.; Baumann, C.; Lenhard, J.; Murray, W. V.; Demarest, K. T.; Kuo,
G.-H. Synthesis and biological evaluation of 3-aryl-3-(4-phenoxy)-
propionic acid as a novel series of G protein-coupled receptor 40
agonists. J. Med. Chem. 2007, 50, 2807−2817.
(9) Christiansen, E.; Urban, C.; Merten, N.; Liebscher, K.; Karlsen,
K. K.; Hamacher, A.; Spinrath, A.; Bond, A. D.; Drewke, C.; Ullrich, S.;
Kassack, M. U.; Kostenis, E.; Ulven, T. Discovery of potent and
selective agonists for the free fatty acid receptor 1 (FFA1/GPR40), a
potential target for the treatment of type II diabetes. J. Med. Chem.
2008, 51, 7061−7064.
(10) Zhou, C. Y.; Tang, C.; Chang, E.; Ge, M.; Lin, S. N.; Cline, E.;
Tan, C. P.; Feng, Y.; Zhou, Y. P.; Eiermann, G. J.; Petrov, A.; Salituro,
G.; Meinke, P.; Mosley, R.; Akiyama, T. E.; Einstein, M.; Kumar, S.;
Berger, J.; Howard, A. D.; Thornberry, N.; Mills, S. G.; Yang, L. H.
Discovery of 5-aryloxy-2,4-thiazolidinediones as potent GPR40
agonists. Bioorg. Med. Chem. Lett. 2010, 20, 1298−1301.
(11) Negoro, N.; Sasaki, S.; Mikami, S.; Ito, M.; Suzuki, M.;
Tsujihata, Y.; Ito, R.; Harada, A.; Takeuchi, K.; Suzuki, N.; Miyazaki, J.;
Santou, T.; Odani, T.; Kanzaki, N.; Funami, M.; Tanaka, T.; Kogame,
A.; Matsunaga, S.; Yasuma, T.; Momose, Y. Discovery of TAK-875: A
potent, selective, and orally bioavailable GPR40 agonist. ACS Med.
Chem. Lett. 2010, 1, 290−294.
(12) Christiansen, E.; Due-Hansen, M. E.; Urban, C.; Merten, N.;
Pfleiderer, M.; Karlsen, K. K.; Rasmussen, S. S.; Steensgaard, M.;
Hamacher, A.; Schmidt, J.; Drewke, C.; Petersen, R. K.; Kristiansen,
K.; Ullrich, S.; Kostenis, E.; Kassack, M. U.; Ulven, T. Structure−
activity study of dihydrocinnamic acids and discovery of the potent
FFA1 (GPR40) agonist TUG-469. ACS Med. Chem. Lett. 2010, 1,
345−349.
(13) Sasaki, S.; Kitamura, S.; Negoro, N.; Suzuki, M.; Tsujihata, Y.;
Suzuki, N.; Santou, T.; Kanzaki, N.; Harada, M.; Tanaka, Y.;
Kobayashi, M.; Tada, N.; Funami, M.; Tanaka, T.; Yamamoto, Y.;
Fukatsu, K.; Yasuma, T.; Momose, Y. Design, synthesis, and biological
activity of potent and orally available G protein-coupled receptor 40
agonists. J. Med. Chem. 2011, 54, 1365−1378.
(14) Walsh, S. P.; Severino, A.; Zhou, C. Y.; He, J. F.; Liang, G. B.;
Tan, C. P.; Cao, J.; Eiermann, G. J.; Xu, L.; Salituro, G.; Howard, A.
D.; Mills, S. G.; Yang, L. H. 3-Substituted 3-(4-aryloxyaryl)-propanoic
acids as GPR40 agonists. Bioorg. Med. Chem. Lett. 2011, 21, 3390−
3394.
(15) Christiansen, E.; Urban, C.; Grundmann, M.; Due-Hansen, M.
E.; Hagesaether, E.; Schmidt, J.; Pardo, L.; Ullrich, S.; Kostenis, E.;
Kassack, M. U.; Ulven, T. Identification of a potent and selective free
fatty acid receptor 1 (FFA1/GPR40) agonist with favorable
physicochemical and in vitro ADME properties. J. Med. Chem. 2011,
54, 6691−6703.
(19) Negoro, N.; Sasaki, S.; Mikami, S.; Ito, M.; Tsujihata, Y.; Ito, R.;
Suzuki, M.; Takeuchi, K.; Suzuki, N.; Miyazaki, J.; Santou, T.; Odani,
T.; Kanzaki, N.; Funami, M.; Morohashi, A.; Nonaka, M.; Matsunaga,
S.; Yasuma, T.; Momose, Y. Optimization of (2,3-dihydro-1-
benzofuran-3-yl)acetic acids: discovery of a non-free fatty acid-like,
highly bioavailable G protein-coupled receptor 40/free fatty acid
receptor 1 agonist as a glucose-dependent insulinotropic agent. J. Med.
Chem. 2012, 55, 3960−3974.
(20) Christiansen, E.; Due-Hansen, M. E.; Urban, C.; Grundmann,
M.; Schroder, R.; Hudson, B. D.; Milligan, G.; Cawthorne, M. A.;
̈
Kostenis, E.; Kassack, M. U.; Ulven, T. Free fatty acid receptor 1
(FFA1/GPR40) agonists: mesylpropoxy appendage lowers lipophi-
licity and improves ADME properties. J. Med. Chem. 2012, 55, 6624−
6628.
(21) Brown, S. P.; Dransfield, P. J.; Vimolratana, M.; Jiao, X.; Zhu, L.;
Pattaropong, V.; Sun, Y.; Liu, J.; Luo, J.; Zhang, J.; Wong, S.; Zhuang,
R.; Guo, Q.; Li, F.; Medina, J. C.; Swaminath, G.; Lin, D. C.-H.;
Houze, J. B. Discovery of AM-1638: A potent and orally bioavailable
GPR40/FFA1 full agonist. ACS Med. Chem. Lett. 2012, 3, 726−730.
(22) Luo, J.; Swaminath, G.; Brown, S. P.; Zhang, J.; Guo, Q.; Chen,
M.; Nguyen, K.; Tran, T.; Miao, L.; Dransfield, P. J.; Vimolratana, M.;
Houze, J. B.; Wong, S.; Toteva, M.; Shan, B.; Li, F.; Zhuang, R.; Lin,
D. C.-H. A potent class of GPR40 full agonists engages the
enteroinsular axis to promote glucose control in rodents. PLoS One
2012, 7, e46300.
(23) Stephens, P. J.; Devlin, F. J.; Pan, J.-J. The determination of the
absolute configurations of chiral molecules using vibrational circular
dichroism (VCD) spectroscopy. Chirality 2008, 20, 643−663.
(24) Stephens, P. J.; Devlin, F. J.; Cheeseman, J. R.; Frisch, M. J.;
Rosini, C. Determination of absolute configuration using optical
rotation calculated using density functional theory. Org. Lett. 2002, 4,
4595−4598.
(25) X-ray data was collected by Frederick J. Hollander and Antonio
DiPasquale at UC Berkeley and submitted to the Cambridge Structural
Database (www.ccdc.cam.ac.uk): CCDC 903315.
(26) Nishiyama, H.; Itoh, Y.; Matsumoto, H.; Park, S. B.; Itoh, K.
New chiral ruthenium bis(oxazolinyl)pyridine catalyst. Efficient
asymmetric cyclopropanation of olefins with diazoacetates. J. Am.
Chem. Soc. 1994, 116, 2223−2224.
(27) Mann, A. Conformational Restriction and/or Steric Hindrance
in Medicinal Chemistry. In The Practice of Medicinal Chemistry, 2nd
ed.; Wermuth, C. G., Ed.; Academic Press: London, U.K., 1996; pp
233−250.
(28) Lin, D. C.-H.; Guo, Q.; Luo, J.; Zhang, J.; Nguyen, K.; Tran, T.;
Dransfield, P. J.; Brown, S. P.; Houze, J. B.; Vimolratana, M.; Jiao, X.
Y.; Wang, Y.; Birdsall, N. J.; Swaminath, G. Identification and
pharmacological characterization of multiple allosteric binding sites on
the FFA1 Receptor. Mol. Pharmacol. 2012, 82, 843−859.
(16) Houze, J. B.; Zhu, L.; Sun, Y.; Akerman, M.; Qiu, W.; Zhang, A.
J.; Sharma, R.; Schmitt, M.; Wang, Y.; Liu, J.; Liu, J.; Medina, J. C.;
Reagan, J. D.; Luo, J.; Tonn, G.; Zhang, J.; Lu, J. Y.-L.; Chen, M.;
Lopez, E.; Nguyen, K.; Yang, L.; Tang, L.; Tian, H.; Shuttleworth, S. J.;
Lin, D. C. H. AMG 837: A potent, orally bioavailable GPR40 agonist.
Bioorg. Med. Chem. Lett. 2012, 22, 1267−1270.
(17) Negoro, N.; Sasaki, S.; Ito, M.; Kitamura, S.; Tsujihata, Y.; Ito,
R.; Suzuki, M.; Takeuchi, K.; Suzuki, N.; Miyazaki, J.; Santou, T.;
Odani, T.; Kanzaki, N.; Funami, M.; Tanaka, T.; Yasuma, T.; Momose,
Y. Identification of fused-ring alkanoic acids with improved
pharmacokinetic profiles that act as G protein-coupled receptor 40/
free fatty acid recptor 1 agonists. J. Med. Chem. 2012, 55, 1538−1552.
(18) Mikami, S.; Kitamura, S.; Negoro, N.; Sasaki, S.; Suzuki, M.;
Tsujihata, Y.; Miyazaki, T.; Ito, R.; Suzuki, N.; Miyazaki, J.; Santou, T.;
Kanzaki, N.; Funami, M.; Tanaka, T.; Yasuma, T.; Momose, Y.
Discovery of phenylpropanoic acid derivatives containing polar
functionalities as potent and orally bioavailable G protein coupled
receptor 40 agonists for the treatment of type 2 diabetes. J. Med. Chem.
2012, 55, 3756−3776.
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