Discovery of phenyl acetamides as potent and selective GPR119 agonists

Article abstract of DOI:10.1016/j.bmcl.2017.01.091

The paper describes the SAR/SPR studies that led to the discovery of phenoxy cyclopropyl phenyl acetamide derivatives as potent and selective GPR119 agonists. Based on a cis cyclopropane scaffold discovered previously, phenyl acetamides such as compound 17 were found to have excellent GPR119 potency and improved physicochemical properties. Pharmacokinetic data of compound 17 in rat, dog and rhesus will be described. Compound 17 was suitable for QD dosing based on its predicted human half-life, and its projected human dose was much lower than that of the recently reported structurally-related benzyloxy compound 2. Compound 17 was selected as a tool compound candidate for NHP (Non-Human Primate) efficacy studies.

Full text of DOI:10.1016/j.bmcl.2017.01.091

Bioorganic & Medicinal Chemistry Letters xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of phenyl acetamides as potent and selective GPR119 agonists
b
a
b
a
a
Cheng Zhu a, , Liping Wang , Yuping Zhu , Zack Zhiqiang Guo , Ping Liu , Zhiyong Hu ,
Jason W. Szewczyk b, Ling Kang b, Gary Chicchi b, Anka Ehrhardt b, Andrea Woods b, Toru Seo b,
Morgan Woods a, Margaret van Heek a, Karen H. Dingley a, Jianmei Pang a, Gino M. Salituro b, Joyce Powell b,
Jenna L. Terebetski a, Viktor Hornak b, Louis-Charles Campeau b, Robert K. Orr b, Feroze Ujjainwalla a,
Michael Miller a, Andrew Stamford b, Harold B. Wood a, Timothy Kowalski a, Ravi P. Nargund a,
Scott D. Edmondson a
⇑
a Early Development and Discovery Sciences, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA
b Early Development and Discovery Sciences, Merck & Co., Inc., 126 East Lincoln Avenue, Rahway, NJ 07065, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The paper describes the SAR/SPR studies that led to the discovery of phenoxy cyclopropyl phenyl aceta-
mide derivatives as potent and selective GPR119 agonists. Based on a cis cyclopropane scaffold discovered
previously, phenyl acetamides such as compound 17 were found to have excellent GPR119 potency and
improved physicochemical properties. Pharmacokinetic data of compound 17 in rat, dog and rhesus will
be described. Compound 17 was suitable for QD dosing based on its predicted human half-life, and its
projected human dose was much lower than that of the recently reported structurally-related benzyloxy
compound 2. Compound 17 was selected as a tool compound candidate for NHP (Non-Human Primate)
efficacy studies.
Received 9 January 2017
Accepted 27 January 2017
Available online xxxx
Keywords:
GPR119 agonist
Type 2 diabetes
Phenyl acetamide
Cis cyclopropane
Ó 2017 Elsevier Ltd. All rights reserved.
Glucose dependent insulin secretion
Diabetes can cause serious health complications such as cardio-
vascular disease, blindness and kidney failure. It is becoming more
common in the United States and worldwide. For example, from
1980 through 2014, the number of Americans with diagnosed dia-
betes has increased fourfold (from 5.5 million to 22.0 million).1
Among diabetic patients, a majority (approximately 90–95%) have
type 2 diabetes (T2D). Therefore, more effective and safer therapies
for type 2 diabetes are needed. G protein-coupled receptor 119
(GPR119) agonists have emerged as a potential new approach for
the treatment of type 2 diabetes.2
GPR119 is present primarily in the pancreas and the intestine.
Activation of GPR119 increases insulin, GLP-1, GIP and PYY secre-
tion.2b GPR119 agonists stimulate insulin release in a glucose-
dependent manner.3 The glucose dependent insulin secretion
(GIDS) mechanism makes GPR119 an attractive target for the treat-
ment of type 2 diabetes with low risk for hypoglycemia. Conse-
quently, GPR119 agonists have been studied extensively and
several compounds have entered clinical trials for the treatment
of diabetes. However, despite the promising effects in preclinical
species (especially in rodents) and enormous efforts by both acade-
mia and many pharmaceutical companies, it is still a challenge to
demonstrate robust glycemic control efficacy in humans.4 So far,
no compound has been reported to progress beyond phase II clinic
trials.5
To increase the probability of success in glycemic control effi-
cacy, we were interested in developing a fixed-dose combination
(FDC) of
a GPR119 agonist with a DPP4 inhibitor such as
sitagliptin.6 It has been reported that in rat models, such combina-
tions provide greater glucose lowering effects than either the
GPR119 agonist or the DPP4 inhibitor alone.7,8 Our previous pre-
clinical candidate 1 (Fig. 1) which had excellent potency, selectivity
and in vivo efficacy,9 was unsuitable for a fixed dose combination
with sitagliptin (QD) due to, (a) a very long half-life in humans
and, (b) poor solubility in, for example, fasted-state simulated
intestinal fluid (FaSSIF)10 which would result in a high likelihood
of a need for the use of enabled formulations in a FDC setting with
sitagliptin. Structure-activity relationship (SAR) and structure-
property relationship (SPR)11 efforts that were focused on reducing
the predicted human t1/2 and improving FaSSIF solubility, while
maintaining good potency at activation of GPR119 led to the dis-
covery of benzyloxy compound 2 (Fig. 1). Compound 2 possessed
excellent GPR119 potency, selectivity, and significantly improved
physicochemical properties compared to its precursor 1.6 The
⇑
Corresponding author.
E-mail address: cheng.zhu@merck.com (C. Zhu).
http://dx.doi.org/10.1016/j.bmcl.2017.01.091
0960-894X/Ó 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Zhu C., et al. Bioorg. Med. Chem. Lett. (2017), http://dx.doi.org/10.1016/j.bmcl.2017.01.091

2
C. Zhu et al. / Bioorganic & Medicinal Chemistry Letters xxx (2017) xxx–xxx
N
N
N
O
N
O
OMe
N
N
N
MeO2S
F
MeO2S
Cl
2
1
h GPR119 EC50 2.1 nM (88%)a
rat PK: t1/2 1.0 h
h GPR119 EC50 3.3 nM (69%)a
rat PK: t1/2 14.7 h
Clint 1000 mL/min/kg
Vdu 54 L/kg
Clint 1446 mL/min/kg
Vdu 1725 L/kg
µ
M
FaSSIF solubility: 21 µM
FaSSIF solubility: 161
LogD 4.9b
LogD 3.5b
Fig. 1. Structure of our GPR119 agonists.6 (a) The percentage in parentheses: % control at max dose. (b) HPLC logD at pH 7.
projected human half-life for compound 2 was ꢀ15 h which was in
the target range for a QD dosing. Its projected human dose (QD),
however, was ꢀ300 mg which was suboptimal as it would need
to be combined with a 200 mg once daily dose of sitagliptin. Herein
we report our continued efforts in this area to improve the GPR119
potency and to further improve the overall pharmacokinetic pro-
files to reduce the projected human dose within this series of
GPR119 agonists.
Compound 2 is a benzyloxy analogue while compound 1 is a
phenoxy derivative. As we reported before,6 changing from a phe-
noxy analogue to the corresponding benzyloxy group resulted in a
favorable drop in lipophilicity and decreased unbound volume of
distribution (Vdu). For example in rat, compound 1 had Vdu 1725,
while compound 2 had Vdu = 54 L/kg which helped reduce its rat
t1/2 (1.0 h vs 14.7 h). However, high intrinsic clearance Clint was
observed for many benzyloxy analogues due to extensive benzylic
oxidative metabolism. Half-life can be shortened by increasing Clint
and/or by decreasing Vdu of a compound. However, increasing Clint
will also lead to an increased QD dose projection and potentially
higher levels of metabolites. Therefore, although the benzyloxy
series was promising in reducing t1/2 and improving FaSSIF solubil-
ity, SAR studies on the original phenoxy lead were revisited in an
effort to keep the Clint and projected human dose in the targeted
range (i.e. <200 mg projected human QD dose).
cis piperidinyl cyclopropyl alcohol 3 via a Mitsunobu reaction.
Then a Negishi reaction of bromide 19 with (2-(tert-butoxy)-2-
oxoethyl)zinc(II) bromide followed by tert-butyl ester deprotection
gave the MOM pyrimidine phenylacetic acid 4. The final product 17
was synthesized by a routine HATU amide coupling reaction.
SAR and SPR results of acetamides synthesized in Schemes 1
and 2 are summarized in Table 1. Our previous preclinical candi-
date 1 is also shown for comparison. We were pleased to find that
secondary amide 5 had excellent GPR119 potency (hGPR119
EC50 = 1.8 nM). However, its FaSSIF solubility (22
lM) remained
as poor as that of compound 1 (21 M). In addition to 5, other sec-
l
ondary amides we synthesized all exhibited poor FaSSIF solubility.
Primary amide 6 (Scheme 2) had reduced GPR119 potency. In con-
trast to primary amide 6 and secondary amide 5, tertiary amide 7
had improved FaSSIF solubility (97 lM) and maintained excellent
GPR119 potency (hGPR119 EC50 = 0.8 nM). Furthermore we were
pleased to find that in rat PK studies, t1/2 of tertiary amide 7
became 4.7 h compared to a very long t1/2 (15 h) of compound 1.
The 3-pyridinyl acetamide 8 (Scheme 2) which has a pyridine moi-
ety as compound 1, was less active than phenyl 7. 3-F substituted 9
(Scheme 2) was also less active (hGPR119 EC50 = 2.2 nM) than 7.
However, 2-F substituted 10 was more potent (hGPR119
EC50 = 0.2 nM) than unsubstituted 7 (hGPR119 EC50 = 0.8 nM).
Compound 10 also had good FaSSIF solubility (137 lM). SAR stud-
As we had already demonstrated that, the cis cyclopropyl piper-
idine scaffold provides several advantages such as improved
GPR119 potency and selectivity,9 we elected to keep this core
intact. Extensive SAR studies were first performed on the left hand
side of the molecule by replacing the pyridinyl sulfone group of 1
with different substituted aromatic rings. Among the many struc-
turally diverse derivatives synthesized, we were pleased to find
that phenyl acetamides provided some promising new directions.
The representative synthesis of the phenyl acetamides is illus-
trated in Scheme 1. (1S,2R) cis piperidinyl cyclopropyl alcohol 3
was converted to phenylacetic acid 4 via a Mitsunobu reaction
with methyl 2-(4-hydroxyphenyl)acetate (or the corresponding F
substituted phenol) followed by methyl ester hydrolysis. The
detailed syntheses of intermediate 3 with different piperidine cap-
ping groups have been described in Ref. 12. Finally, amide bond
formation with EDC, HOBt or HATU afforded a variety of phenyl
acetamide final products.
Because of the commercial availability of some acetamide phe-
nol starting materials, a few acetamide final products (such as 6
and 9, Scheme 2) were directly synthesized via a Mitsunobu reac-
tion with chloropyrimidine cis piperidinyl cyclopropyl alcohol 3.
The 3-pyridinyl analogue 8 was synthesized by a nucleophilic aro-
matic substitution reaction between chloropyridinyl azetidine
acetamide and chloropyrimidine cis piperidinyl cyclopropyl alco-
hol 3.
ies from an amide library synthesis revealed that while a variety of
amines were tolerated for GPR119 potency, azetidine amide 10
was one of the most potent analogues (for example, compared with
hydroxyl azetidine 11 and piperidine amide 12). However with a
long projected human half-life (ꢀ46 h based on allometric scaling
from rat), compound 10 was still not ideally matched for a QD
fixed-dose combination (FDC) partner with sitagliptin. Although
hydroxyl azetidine 11 had a reduced rat t1/2 (3.5 h), its hERG activ-
ity (hERG IC50 = 5.3 lM) remained a concern. Chloropyrimidine
compounds 7–12 all had moderate hERG inhibition. Many histori-
cal GPR119 agonists have struggled with hERG inhibition as well as
solubility issues,14 and some even had CNS side effects, potentially
due to off-target activities that accompany their highly lipophilicic
features.5,8b
We next turned our attention to piperidine capping groups on
the right-hand side (RHS) of the molecule such as ethylpyrimidine,
oxadiazole and carbamates which are structure moieties of some
clinical GPR119 agonists.5 Ethylpyrimidine 13 maintained excel-
lent potency (hGPR119 EC50 = 0.4 nM), however, with no improve-
ment in hERG selectivity. Methylcyclopropyl carbamate 14 was
less active in an IKr binding assay (hERG IC50 = 23 lM), however,
it was also less potent at GPR119 (hGPR119 EC50 = 3.3 nM). More-
over, in a cardiac ion channel blockade activity assay,15 functional
hERG inhibition for 14 was determined to be more potent (hERG
IC50 = 8.6 lM) than in IKr binding assay. Isopropyl oxadiazole
Another alternative synthesis was described in Scheme 3. Read-
ily available bromo phenol 18 was coupled with MOM pyrimidine
(15) also reduced potency (hGPR119 EC50 = 2.0 nM) relative to
the chloropyrimidine 10, and hERG selectivity was still suboptimal
Please cite this article in press as: Zhu C., et al. Bioorg. Med. Chem. Lett. (2017), http://dx.doi.org/10.1016/j.bmcl.2017.01.091

C. Zhu et al. / Bioorganic & Medicinal Chemistry Letters xxx (2017) xxx–xxx
3
O
N
c
a,b
O
R
HO
N
R
HO
3
4
H or F
O
N
N
O
N
N
O
F
O
N
N
N
H
Cl
N
Cl
5
7
O
N
N
F
O
O
N
N
N
N
O
O
N
N
N
N
Cl
N
N
Cl
Et
10
12
11
13
HO
F
O
N
N
F
O
O
N
N
Cl
F
O
N
Me
Me
F
O
N
O
N
Me
N
O
O
O
O
N
O
N
N
N
N
N
15
17
14
16
F
O
N
N
F
O
N
O
N
OMe
OMe
F
Scheme 1. Representative synthesis of the acetamides. Reagents and conditions: (a) methyl 2-(4-hydroxyphenyl)acetate, PPh3, DIAD or di-tert-butyl azodicarboxylate, DCM,
i
rt; (b) LiOH, THF/MeOH/H2O, rt; (c) amine, EDC or HATU, Pr2NEt, DMF or DCM, rt.
OH
Cl
O
N
N
a
O
O
O
N
H2N
H2N
Cl
6
8
b
O
N
N
O
N
N
N
N
N
Cl
OH
F
c
O
F
N
N
O
O
N
N
N
Cl
9
Scheme 2. Synthesis of acetamide 6,
8 and 9. Reagents and conditions: (a) chloropyrimidine intermediate 3, di-tert-butyl azodicarboxylate, DCM, rt, 33%; (b)
chloropyrimidine intermediate 3, NaHMDS, DMF, 150 °C, 4%; (c) chloropyrimidine intermediate 3, di-tert-butyl azodicarboxylate, DCM, rt, 71%.
(hERG IC50 = 7.0
l
M). Furthermore, the projected human half-lifes
the corresponding MOM pyrimidine compound 16 not only had
excellent FaSSIF solubility (152 M) and GPR119 potency
(hGPR119 EC50 = 0.7 nM), but also reduced hERG activity (hERG
IC50 = 19 M). Since 2-F substitution improved GPR119 potency
of several isopropyl oxadiazole phenylacetamides including 15
were generally projected to be too short to support a QD human
dose less than 200 mg.
l
l
We previously reported that a MOM pyrimidine improved solu-
bility in the benzyloxy series relative to the corresponding
chloropyrimidine RHS moiety.6 We were pleased to discover that
(compound 10 vs 7), the 2,6-difluoro analogue 17 was synthesized.
Compound 17 now had hGPR119 EC50 = 0.2 nM. In IKr binding
assay, its hERG IC50 = 9.2 lM. In cardiac ion channel blockade activ-
Please cite this article in press as: Zhu C., et al. Bioorg. Med. Chem. Lett. (2017), http://dx.doi.org/10.1016/j.bmcl.2017.01.091

4
C. Zhu et al. / Bioorganic & Medicinal Chemistry Letters xxx (2017) xxx–xxx
F
OH
F
O
N
N
b, c
a
N
O
Br
Br
F
18
F
19
d
F
O
N
N
F
O
N
N
O
O
N
N
N
HO
F
OMe
OMe
F
17
4
MOM pyrimidine
Scheme 3. An alternative synthesis of compound 17. Reagents and conditions: (a) MOM pyrimidine intermediate 3, di-tert-butyl azodicarboxylate, DCM, rt; (b) (2-(tert-
i
butoxy)-2-oxoethyl)zinc(II) bromide, X-Phos Pre-catalyst, 65 °C; (c) TFA, DCM, 53% over three steps; (d) azetidine, HATU, Pr2NEt, DMF, rt, 72%.
Table 1
SAR results of the acetamides synthesized in Schemes 1 and 2 (nd = not determined).
c
Comps
hGPR119a EC50 (nM)
mGPR119a EC50 (nM)
FaSSIFb
(l
M)
hERG IC50
(lM)
rat t1/2 (h)
1
5
6
7
8
9
10
11
12
13
14
15
16
17
3.3 (69%)
1.8 (104%)
67 (85%)
6.5 (95%)
1.5 (91%)
16 (68%)
21
22
nd
97
83
65
137
144
124
140
138
126
152
139
9.9
>60
nd
15
nd
nd
4.7
nd
nd
6.9
3.5
nd
nd
1.6
1.8
1.9
3.5
0.8 (82%)
9.4 (112%)
2.2 (106%)
0.2 (106%)
0.8 (89%)
1.5 (116%)
0.4 (103%)
3.3 (127%)
2.0 (78%)
0.7 (82%)
0.2 (91%)
0.5 (93%)
5.1 (133%)
1.6 (91%)
0.4 (146%)
6.7 (110%)
2.2 (92%)
0.84 (111%)
6.6 (115%)
6.7 (102%)
1.6 (90%)
0.8 (116%)
7.4
2.1
3.5
3.3
5.3
3.3
3.2
23
7.0
19
9.1
a
Human and mouse GPR119 EC50 values are means of at least 2 independent experiments except compound 6 and 8. The percentage in parentheses, % control at max dose;
magnitude of cAMP stimulation expressed in % compared to an internal agonist control; the control was defined to have 100% cAMP stimulation.
b
Kinetic solubility in fasted-state simulated intestinal fluid (FaSSIF) at pH 6.5.
IKr binding assay, Ref. 13.
c
ity assay,15 functional hERG inhibition was confirmed to be mild
(Clint was 1104, 60, 319, 42 mL/min/kg in rat, dog, rhesus and
(hERG IC50 = 12
(3.5 h).
l
M). Compound 17 also had a favorable rat t1/2
human liver microsomes), compound 17 was significantly more
stable in rat and rhesus liver microsomes. As a result, compound
17 had improved pharmacokinetic profiles in rat and rhesus mon-
key, which are shown in Table 2.
Because of its excellent GPR119 potency, good hERG selectivity
and favorable rat t1/2, compound 17 was scaled-up and further pro-
filed. The synthetic protocols described in Schemes 1 and 3 were
both suitable for a multi-gram scale synthesis of compound 17.
An off-target screen was performed against an extensive panel of
168 receptors, ion channels, and enzymes, and no off-target activ-
ities were found with IC50s < 10
tive over CYP3A4 (IC50 > 50 M) and hPXR (EC50 > 30
equilibration solubility studies, crystalline 17 had FaSSIF solubility
0.051 mg/mL (vs 0.009 mg/mL of compound 1), which confirmed
the improvements observed in the kinetic FaSSIF solubility data
In rat PK studies, compound 17 possessed lower in vivo
unbound clearance than compound 2 (430 vs 1000 mL/min/kg).
Previously, compound 2 had low bioavailability in rat and rhesus
(27% and 5%), likely due to first-pass metabolism. In contrast, the
bioavailability of compound 17 was improved to 80% (rat) and
44% (rhesus). In mouse oral glucose tolerance test (oGTT) dose
titration PK/PD studies,17 the MEDmax (minimal efficacious dose
for maximal efficacy) for 17 was determined to be 0.1 mpk com-
pared to the MEDmax of compound 2 at 3 mpk. The mouse oGTT
efficacy was ablated in GPR119À/À mice at a suprapharmacological
dose of 3 mpk, which confirmed that the efficacy was GPR119-
mediated. Compound 17 also had low rat oGTT MEDmax that was
0.3 mpk. Based on mouse oGTT MEDmax which was 0.1 mpk, and
the blood concentration of 17 at 90 min post-dosing at 0.1 mpk
was 10 nM in mice, the target plasma trough in humans for acute
l
M. Compound 17 was also selec-
l
l
M).16 In
(139 lM vs 21 lM) and verified that compound 17 indeed exhib-
ited improved FaSSIF solubility compared to compound 1.
In liver microsomal stability studies, the in vitro intrinsic clear-
ance (Clint) of compound 17 was determined to be 189, 39, 44, and
39 mL/min/kg in rat, dog, rhesus and human liver microsomes,
respectively. Compared with the previous benzyloxy compound 2
Table 2
Pharmacokinetic profiles of compound 17.
Species
PPBa (% unbound)
Clp (mL/min/kg)
Vd (L/kg)
t1/2 (h)
F (%)
Rat
Dog
Rhesus
6.7%
5.5%
8.0%
29
2.0
14
4.8
4.3
3.5
3.5
29
7.6
80
55
44
a
Human PPB (% unbound): 3.8%. PPB data reported in Ref. 6 were screening assay data. For comparison reason, PPB data reported herein were also screening assay data.
Please cite this article in press as: Zhu C., et al. Bioorg. Med. Chem. Lett. (2017), http://dx.doi.org/10.1016/j.bmcl.2017.01.091

C. Zhu et al. / Bioorganic & Medicinal Chemistry Letters xxx (2017) xxx–xxx
5
F
O
N
N
O
N
N
O
N
OMe
N
N
N
MeO2S
Cl
F
17
1
h GPR119 EC50 0.2 nM (91%)a
rat PK: t1/2 3.5 h
h GPR119 EC50 3.3 nM (69%)a
rat PK: t1/2 14.7 h
Clint 430 mL/min/kg
Vdu 72 L/kg
Clint 1446 mL/min/kg
Vdu 1725 L/kg
µ
M
FaSSIF solubility: 21 µM
FaSSIF solubility: 139
LogD 4.1b
LogD 4.9b
Fig. 2. From compound 1–17. (a) The percentage in parentheses: % control at max dose. (b) HPLC logD at pH 7.
efficacy was estimated to be ꢀ6 nM.18 The predicted human half-
References
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human dose (QD) was <10 mg, which is much lower than
ꢀ300 mg of compound 2.19 The predicted PK of 2 and 17 are very
similar, with the decreased dose resulting from the significantly
increased potency and thus reduced plasma trough target of 17.
One major issue for the development of GPR119 agonists for the
treatment of type 2 diabetes is the poor translation from rodent
in vivo efficacy models to human clinical trials.4,5 Species differ-
ences in pharmacology between mouse and human has been
reported.20 Consequently, we were also interested in identification
of a suitable tool compound for NHP (non-human primate) studies
to further support PD translation of GPR119 pharmacology to
humans. Compound 17 possesses excellent rhesus GPR119 potency
(rhesus GPR119 EC50 = 0.1 nM) and an excellent rhesus PK profile,
and was therefore selected for further profiling in rhesus glycemic
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In summary, starting from our previous preclinical candidate 1,
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acetamide lead with improved physical properties such as FaSSIF
solubility (Fig. 2). Incorporation of 2,6 di-F substitution and an aze-
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those in vivo pharmacodynamic studies in rhesus will be reported
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16. Pregnane X receptor (PXR) is a nuclear receptor known to regulate expression
of drug-metabolizing enzymes including cytochrome P450 (CYP450), see: Chu
V et al. Drug Metab Dispos. 2009;37:1339–1354.
17. Compounds were tested in vivo using an oral glucose tolerance test (oGTT) in
eleven-week old, lean C57BL/6 Tac mice (n = 8/group). Overnight fasted mice
were administered compound by oral gavage; vehicle: PEG400/23.5% HPBCD
(15/85 v/v). 30 min later, they received an oral glucose challenge (3 g/kg).
Blood glucose was measured via tail nick using a glucometer at 0, 20, 40, and
60 minutes post-glucose challenge. The area under the curve (AUC) for the
glucose response was calculated for each mouse. The glucose AUC of compound
treated mice was compared to that of vehicle-treated mice using an unpaired
Student’s t-test or One-Way ANOVA where appropriate. The data is expressed
as the % change of the Glucose AUC relative to vehicle.
18. The human plasma trough target was estimated from the mouse blood
concentration at 90 min (10 nM) using a blood/plasma ratio of 0.55 and
adjustment for potency and plasma protein binding differences between mice
and humans.
19. Using microsomal stability data across species, the predicted human plasma
clearance was ꢀ4 mL/min/kg. The Vd (ꢀ4.2 L/kg) and bioavailability (ꢀ60%)
were estimated from preclinical species.
Acknowledgments
We would like to thank Dr. Greg Morriello, Mr. Lehua Chang,
Mr. Chris Moyes and Mr. Nam Fung Kar for intermediate 3 synthe-
ses. Cheng Zhu would like to thank Dr. Milana Maletic, Mr. Kake
Zhao and Mrs. Wanying Sun for helpful discussions.
20. Scott JS, Brocklehurst KJ, Brown HS, et al. Bioorg Med Chem Lett. 2013;23:3175.
Please cite this article in press as: Zhu C., et al. Bioorg. Med. Chem. Lett. (2017), http://dx.doi.org/10.1016/j.bmcl.2017.01.091