Discovery of AM-6226: A Potent and Orally Bioavailable GPR40 Full Agonist That Displays Efficacy in Nonhuman Primates

Article abstract of DOI:10.1021/acsmedchemlett.8b00213

GPR40 (FFA1) is a G-protein-coupled receptor, primarily expressed in pancreatic islets and enteroendocrine L-cells, and, when activated, elicits increased insulin secretion only in the presence of elevated glucose levels. We recently reported the discovery of AM-1638 (2), a full agonist of GPR40. Herein, we present further structure-activity relationships progressing from AM-1638 (2) to AM-6226 (14) that possesses a profile acceptable for dosing cynomolgus monkeys. The GPR40 full agonist AM-6226 (14) is the first molecule to display significant glucose lowering in cynomolgus monkeys providing additional evidence that GPR40 full agonists afford access to a powerful mechanism for maintaining glycemic control.

Full text of DOI:10.1021/acsmedchemlett.8b00213

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Letter
Discovery of AM-6226. A Potent and Orally Bioavailable GPR40
Full Agonist that Displays Efficacy in Non-Human Primates.
Sean P Brown, Paul J Dransfield, Marc Vimolratana, Liusheng Zhu, Jian Luo, Jane Zhang, XianYun Jiao,
Vatee Pattaropong, Simon Wong, Run Zhuang, Gayathri Swaminath, Jonathan B Houze, and Daniel C.-H. Lin
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.8b00213 • Publication Date (Web): 06 Jun 2018
Downloaded from http://pubs.acs.org on June 6, 2018
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Discovery of AM-6226. A Potent and Orally Bioavailable GPR40
Full Agonist that Displays Efficacy in Non-Human Primates.
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Sean P. Brown,* Paul Dransfield,* Marc Vimolratana, Liusheng Zhu, Jian Luo, Jane Zhang, XianYun
Jiao, Vatee Pattaropong, Simon Wong, Run Zhuang, Gayathri Swaminath, Jonathan B. Houze, Daniel
C.ꢀH. Lin.*
Amgen Discovery Research, Department of Medicinal Chemistry, One Amgen Center Drive, Thousand Oaks, CA 91320,
United States
KEYWORDS: GPR40, full agonist, AMꢀ6226, AMꢀ1638, AMG 837, insulin secretagogue, FFA1
Supporting Information Placeholder
ABSTRACT: GPR40 (FFA1) is a Gꢀproteinꢀcoupled receptor, primarily expressed in pancreatic islets and enteroendocrine Lꢀcells,
when activated elicits increased insulin secretion only in the presence of elevated glucose levels. We recently reported the discovꢀ
ery of AMꢀ1638 (2), a full agonist of GPR40. Here in, we preꢀ
sent further structure–activity relationships progressing from
AMꢀ1638 (2) to AMꢀ6226 (14) that possesses a profile acꢀ
ceptable for dosing cynomolgus monkeys. The GPR40 full
agonist AMꢀ6226 (14) is the first molecule to display signifiꢀ
cant glucose lowering in cynomolgus monkeys providing addiꢀ
tional evidence that GPR40 full agonists afford access to a
powerful mechanism for maintaining glycemic control.
Type II diabetics lose their ability to maintain glucose homeꢀ
ostasis due to multiple metabolic defects.1 GPR40 is a Gꢀ
proteinꢀcoupled receptor, primarily expressed in pancreatic
islets βꢀcells and enteroendocrine Lꢀcells2 that possess the
ability to modulate several metabolic defects when activated.
Mediumꢀ to longꢀchain fatty acids bind to and elicit GPR40
to increase insulin secretion from βꢀcells and increased seꢀ
cretion of the gut hormones, glucagonꢀlike peptide 1 (GLPꢀ
which to assess improvements in intrinsic efficacy (Figure
1). Optimization of the full agonist series afforded
AMꢀ1638 (2) that displays greater antidiabetic efficacy in
several rodent diabetic models compared to partial agonist
1,13 providing compelling evidence that GPR40 full agonists
engage a powerful mechanism for maintaining glycemic
control.
100
AMGꢀ837
,4,5
1) and glucoseꢀdependent insulinotropic peptide (GIP).3
DHA
80
60
40
20
0
Agonists of GPR40 present low risk of hypoglycemia and
have been considered by multiple groups leading to the disꢀ
, , , , ,
covery of multiple clinical candidates.4 5 6 7 8 9 These clinical
-10
-9
-8
-7
-6
-5
-4
-3
candidates, such as AMG 837 (1), are all partial agonists of
log [M]
,
,
GPR40. We previously described the discovery of 1,10 11 12
that demonstrations antidiabetic activity in rodent models
without exhibiting hypoglycemia. Favorable pharmacokinetꢀ
ic properties and efficacy of 1 led to its selection for clinical
evaluation. We became interested in evaluating GPR40 full
agonists in a nonꢀhuman primate model of diabetes, since
partial agonist 1‘s ability to maintain glycemic control was
being tested in a clinical setting.
100
AMꢀ1638
DHA
80
60
40
20
0
-10
-9
-8
-7
-6
-5
-4
-3
log(M)
We recently described a series of GPR40 full agoꢀ
,
,
,
,
nists13 14 15 16 17 that were identified from compounds syntheꢀ
sized in the discovery of 1 by evaluating them in CHO cells
transfected with lower levels of GPR40 expression plasmid
(0.05 µg). This assay provides greater dynamic range with
Figure 1. The effect of AMG 837 (1), AMꢀ1638 (2) and doꢀ
cosahexaenoic acid (DHA) in CHO cells transfected with 0.05
µg of GPR40 expression plasmid.
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In an effort to improve the potency and pharmacokinetic
vitro (Table 3, 18, EC50= 0.10 µM) and pharmacokinetic
profile (Table 4, 18), albeit a lower oral bioavailibility.
properties of full agonist 2, we initiated further optimization
of the full agonist series of compounds. Saturation of the
cyclopentene ring led to an improvement in potency in the
(R)ꢀenantiomeric series (Table 1, 4, EC50= 0.08 µM), while
loss in potency was observed in the (S)ꢀenantiomeric series
(Table 1, 5, EC50= 0.31 µM). While maintaining the 2,2ꢀ
dimethylꢀ(R)ꢀcyclopentane moiety we next turned our attenꢀ
tion to the βꢀsubstituent from the carboxylic acid (Table 2).
Previous optimization had revealed that small alkyl substituꢀ
ents were preferred at this position. Reducing the size of the
βꢀsubstituent to a hydrogen (6, EC50= 0.45 µM) or methyl (7,
EC50= 0.17 µM) led to a loss in potency. βꢀSubstituents
with similar size to that of the cyclopropane of full agonist 4
displayed similar potency (8ꢀ11, EC50= 0.08ꢀ0.11 µM). The
two most potent substituents, the ethyl and cyclopropane,
were selected for further optimization, while evaluation of
their entipodes displayed a significant decrease in potency
and efficacy (12, 13; EC50= 1.96, 1.83 µM; 76%, 89%).
Due to the similar in vitro profiles of the fluorinated comꢀ
pounds 14 and 18, 14 was selected for further pharmacokiꢀ
netic evaluation in higher species because of the greater exꢀ
posure achieved in rats (AUC= 8.22 µM·h). Full agonist 14
displayed both low clearance and good oral bioavailability in
dog and cynomologus monkeys (Table 5; Cl=0.21, 0.22
L/h/kg; %F=62, 91), respectively. This profile is a signifiꢀ
cant improvement over compound 2 with a >4ꢀfold imꢀ
provement in AUC while fraction unbound in plasma are
similar between the two compounds (Table 5). We deemed
the profile acceptable to evaluate the antidiabetic activity of
full agonist 14, that we have named AMꢀ6226, in a nonꢀ
human primate model of diabetes.
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Table 2. Exploration of βꢀSubstituent SAR
F
Table 1. The Effect of Biphenyl Modification on GPR40 Activity in the
Presence 100% Human Serum
MeO
R
O
O
OH
Me
Me
R
Compound
GPR40 EC50
(ꢁM)a
Efficacy
(%)a,b
H
6
7
0.45
0.17
0.08
0.11
0.08
0.09
0.10
1.96
1.83
120
106
102
100
101
100
98
Me
Et
8
nꢀPr
9
4
10
11
12
13
a Mean of at least two runs; b % Compared to reference agonist 2.
To decrease the electron density of the oxyꢀaryl ring, we
evaluated fluorination of the four possible positions. Inꢀ
stallment of a fluorine at the 2 and 5ꢀpositions provided full
agonists with a minimal loss in potency (Table 3; 14, 0.12
µM; 16, 0.09 µM), while fluorination at the 4 and 6ꢀ
positions led to more significant losses in potency (Table 3;
15, 0.21 µM; 17, 0.74 µM). Because they maintained potenꢀ
cy the pharmacokinetic properties of the fluorinated full
agonist 14 and 16 were evaluated (Table 4). Full agonist 14
displayed low iv clearance and high oral bioavailability.
Because of this favorable profile the βꢀethyl substituent was
exchanged for a cyclopropane that displayed a similar in
Et
76
89
a
Mean of at least two runs; b % Compared to reference agonist
2.
The synthesis of full agonist 14 begins with hydrogenation
of the triꢀsubstituted olefin 19 (Scheme 1), followed by ester
reduction, which yielded racemic alcohols in excellent yield.
Separation of the enantiomers and subsequent chlorination
yielded the desired benzylic chloride 20. Condensation of
2
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Table 5. The Pharmacokinetic Properties of Full Agonist 14
aldehyde 21 with Meldrum’s acid yielded olefin 22, and
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4
5
6
7
8
9
subsequent conjugate addition of ethyl magenesium bromide
yielded 23. Hydroylsis of the diester, removal of methyl
ether using dodecylthiol, subsequent esterification, and chiꢀ
ral separation delivered 24 in good overall yield. Alkylation
of 24 with 20, followed by hydrolysis yielded AMꢀ6226.
oral dose
(mg/kg)
Comp. Species Fu
oral AUC
Cl
Vdss iv t % F
½
(ꢁM—h) (L/h/kg) (L/kg) (h)
2
2
2
rat
rat
0.010
0.003
15.1
8.22
11.6
18.8
80.4
0.91
1.1 1.8 72
14
14
2
0.33 0.81 2.0 72
0.21 0.68 4.1 62
Sitagliptin and 14 were orally dosed to prediabetic cynomolꢀ
gus monkeys selected from a highꢀfat feed colony. The
GPR40 full agonist 14 display significant glucose lowering
during an oral glucose tolerance test (OGTT) at 1 and 10
mg/kg (Figure 2). Moreover, full agonist 14 and the antidiaꢀ
betic drug sitagliptin afforded similar reduction in plasma
glucose AUC (18% vs. 13%) when 10 mg/kg of either comꢀ
pound was administered orally.
2
dog 0.034
cyno 0.012
cyno 0.017
10
10
0.81
0.22
2.0 2.1 71
0.5 3.3 91
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14
a Administered at a dose of 0.5 mg/kg, iv. Data are expressed as mean
values (n = 3).
Scheme 1. a
Table 3. Evaluation of ArylꢀFluorine Substitutions
F
MeO
R
F
O
2
5
O
OH
Me
Me
6
4
R
F
GPR40 EC50 Efficacy
Compound
Position
(ꢁM)a
0.08
0.12
0.21
0.09
0.74
0.10
(%)a,b
102
104
100
105
82
Et
Et
8
none
14 (AMꢀ6226)
2
4
5
6
2
Et
Et
Et
15
16
17c
18
100
a Mean of at least two runs; b % Compared to reference agonist 2.
c Compound 17 contains a 5,5ꢀdimethylꢀ1ꢀcyclopentenꢀ1ꢀyl moiety
instead of the (1R)ꢀ2,2ꢀdimethylcyclopentyl moiety.
a Reagents and conditions: (a) Pd/C, H2O, MeOH, 90%; (b) LiAlH4,
THF, 0 °C, 96%; Chiral separation of enantiomers; Analytical column
(ChiracelꢀOD (2%IPA in hexane, 45 min run) Peak 1ꢀ15.5 mins, Peak
2ꢀ38.0 mins) (c) SOCl2, CH2Cl2, 87%, (d) C6H8O4, H2O, 90°C, 59%,
(e) EtMgBr, THF, 0°C, 93%, (f) DMF/H2O (10/1), 91%, (g), C12H10S,
NaOH, NMP, 125°C, 88%, (h) H2SO4, MeOH, 80°C, 90%, (i) chiral
HPLC (Chiralcel OD column, 3% IPA/hexane, detection at 220 nm) to
afford two seperable peaks, 40% for each peak; (j) 20, H2O, Cs2CO3,
DMF; (k) LiOH, EtOH, H2O, 95% over 2 steps.
Table 4. Rat Pharmacokinetic Properties of Full Agonistsa
In conclusion, we have described the further optimization of
GPR40 full agonists resulting in the identification of
AMꢀ6226 (14) that displays an improved pharmacokinetic
profile and was suitable for evaluation in cynomolgus monꢀ
keys. The antiꢀdiabetic activity that full agonist 14 exhibits
in cynomolgus monkeys along with the previously disclosed
efficacy of GPR40 full agonists in rodent models of diabetes
provides compelling evidence that GPR40 full agonists afꢀ
a Administered at a dose of 0.5 mg/kg, iv; 2 mg/kg, po, in rats. Data are
expressed as mean values (n = 3).
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ford access to a mechanism for maintaining glycemic control
and potential for the treatment of type II diabetic patients.
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Vehicle
Sitagliptin 10 mg/kg
AMꢀ6226 0.1 mg/kg
AMꢀ6226 1 mg/kg
AMꢀ6226 10 mg/kg
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Corresponding Author
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Y. Discovery of TAKꢀ875: A potent, selective, and orally bioaꢀ
vailable GPR40 agonist. ACS Med. Chem. Lett. 2010, 1, 290–
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Corresponding Author: *To whom correspondence should
be
addressed. sebrown@amgen.com, pdransfi@amgen.com,
dclin@amgen.com
7
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