Discovery of novel 2-[(4-hydroxy-6-oxo-2,3-dihydro-1H-pyridine-5-carbonyl)amino]acetic acid derivatives as HIF prolyl hydroxylase inhibitors for treatment of renal anemia

Article abstract of DOI:10.1016/j.bmcl.2018.04.039

Prolyl hydroxylase domain-containing protein (PHD) inhibitors are useful as orally administered agents for the treatment of renal anemia. Based on the common structures of known PHD inhibitors, we found novel PHD inhibitor 1 with a 2-[(4-hydroxy-6-oxo-2,3

Full text of DOI:10.1016/j.bmcl.2018.04.039

Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of novel 2-[(4-hydroxy-6-oxo-2,3-dihydro-1H-pyridine-
5-carbonyl)amino]acetic acid derivatives as HIF prolyl hydroxylase
inhibitors for treatment of renal anemia
Makoto Hamada a, , Tetsuo Takayama a,d, Tsuyoshi Shibata a,e, Akira Hiratate a,f, Masato Takahashi a,g
,
⇑
Miyoko Yashiro a, Noriko Takayama b, Lisa Okumura-Kitajima b, Hiroko Koretsune b, Hiromitsu Kajiyama b,
Takumi Naruse b, Sota Kato b, Hiroki Takano c, Hiroyuki Kakinuma a
a Chemistry Laboratories, Taisho Pharmaceutical Co., Ltd, 1-403 Yoshino-cho, Kita-ku, Saitama 331-9530, Japan
b Pharmacology Laboratories, Taisho Pharmaceutical Co., Ltd, 1-403 Yoshino-cho, Kita-ku, Saitama 331-9530, Japan
c Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co., Ltd, 1-403 Yoshino-cho, Kita-ku, Saitama 331-9530, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Prolyl hydroxylase domain-containing protein (PHD) inhibitors are useful as orally administered agents
for the treatment of renal anemia. Based on the common structures of known PHD inhibitors, we found
novel PHD inhibitor 1 with a 2-[(4-hydroxy-6-oxo-2,3-dihydro-1H-pyridine-5-carbonyl)amino]acetic
acid motif. The PHD2-inhibitory activity, lipophilicity (CLogP), and PK profiles (hepatocyte metabolism,
protein binding, and/or elimination half-life) of this inhibitor were used as the evaluation index to opti-
mize the structure and eventually discovered clinical candidate 42 as the suitable compound. Compound
42 was demonstrated to promote the production of erythropoietin (EPO) following oral administration in
mice and rats. The predicted half-life of this compound in humans was 1.3–5.6 h, therefore, this drug may
be expected to administer once daily with few adverse effects caused by excessive EPO production.
Ó 2018 Elsevier Ltd. All rights reserved.
Received 20 March 2018
Accepted 14 April 2018
Available online xxxx
Keywords:
Prolyl hydroxylase domain-containing
protein (PHD) inhibitors
Hypoxia inducible factor (HIF)
Erythropoietin (EPO)
Renal anemia
Anemia is characterized by a reduced level of hemoglobin in the
blood and often manifests as palpitations, shortness of breath and/
or dizziness in the short term, reducing the Quality of Life (QoL). In
patients with chronic kidney disease (CKD), the hemoglobin level
in the blood decreases in parallel with progression of the underly-
ing disease state (so-called renal anemia). Several factors are
involved in its development, one of which is a decrease in the
amount of erythropoietin (EPO) produced in the kidney due to
renal function impairment.1 EPO is a hormone associated with
the production, regeneration, and differentiation of red blood cells.
The main site of production of this hormone in the kidney is the
peritubular interstitial cells.2,3 Erythropoiesis-stimulating agents
(ESAs), such as recombinant human EPO and related products have
been used for the treatment of renal anemia. These agents not only
improve the QoL by improving the hemoglobin (Hb) level, but have
also been reported to slow down the decline of renal function.4,5
However, there are also several problems associated with the use
of ESAs; its routes of administration are limited to intravenous or
subcutaneous injection, they are expensive, and their efficacy
may weaken because of the formation of antibodies. Thus, the
development of orally available small-molecular-drugs has been
sought.
Physiologically, production of EPO is induced by hypoxia-indu-
cible factor (HIF). HIF is a heterodimer consisting of an
a subunit
and b subunit. It controls hematopoietic factors (EPO and iron
metabolism-related enzymes), glucose metabolism-related factors,
angiogenic growth factors, cell cycle and survival, inflammation,
etc.6,7 Under normoxia, HIF degrades through proteasomal path-
⇑
Corresponding author.
E-mail address: mak-hamada@taisho.co.jp (M. Hamada).
Present address; Licensing & Business Development, Taisho Pharmaceutical Co.,
way because the proline residue of the
a subunit is rapidly hydrox-
d
ylated by prolyl hydroxylase domain-containing protein (PHD).8,9
PHD inhibitors are speculated to improve anemia via causing sta-
bilization of HIF, and are expected as therapeutic agents for renal
anemia and a wide range of other diseases. A number of research
academies and pharmaceutical companies have been engaged in
research to develop an orally available small-molecule drug for
the treatment of renal anemia in place of ESA,10,11 and several
Ltd, 3-24-1, Takada, Toshima-ku, Tokyo 170-8633, Japan.
e
Present address; Pharmaceutical Science Laboratories, Taisho Pharmaceutical Co.,
Ltd, 1-403 Yoshino-cho, Kita-ku, Saitama 331-9530, Japan.
f
Present address; Intellectual Property, Taisho Pharmaceutical Co., Ltd, 3-24-1,
Takada, Toshima-ku, Tokyo 170-8633, Japan.
g
Present address; Research Support, Taisho Pharmaceutical Co., Ltd, 1-403
Yoshino-cho, Kita-ku, Saitama 331-9530, Japan.
https://doi.org/10.1016/j.bmcl.2018.04.039
0960-894X/Ó 2018 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Hamada M., et al. Bioorg. Med. Chem. Lett. (2018), https://doi.org/10.1016/j.bmcl.2018.04.039

2
M. Hamada et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
Fig. 1. PHD inhibitors for which late-phase clinical trials have been reported.
Fig. 3. Model of 1 docking with the active site on PHD2.22
compounds such as roxadustat, daprodustat, vadadustat, and
molidustat (Fig. 1) have been investigated in the late stage of clin-
ical development.12–14
We surmised that the aromaticity of the central core is not neces-
sary to obtain PHD2-inhibitory activity. After several structural
conversions, we discovered compounds in which it was replaced
by a partially saturated heterocyclic structure. As a result, we dis-
covered compound 1, derivatives of which were easy to synthe-
size; this compound was shown to inhibit PHD2 and induce EPO
production in a mouse model following oral administration. The
predicted binding mode of 1 with the active site of PHD2 is shown
in Fig. 3. Cyclohexane and (1,10-biphenyl)-4-ylmethyl substituents
exist outside the pocket of the enzyme and allow various conver-
sions. Therefore, we thought that it would be possible to adjust
the activity and physical properties by modification of the
substituents.
According to the European clinical practice guideline for anemia
in chronic kidney disease, it is recommended that the Hb level not
be increased to over 13 g/dL, so as to avoid increase in the risk of
development of cardiovascular events.15 Rapid fluctuations of the
Hb level (i.e., increase/decrease by ꢀ1 g/dL within 2 weeks)16 and
the ESA dose17 have also been identified as possible risk factors.
Long-term PHD inhibition is associated with the risk of poly-
cythemia-related events. Furthermore, as HIF is involved in the
regulation of a variety of genes, unnecessary/excessive stabiliza-
tion of HIF could be associated with diverse adverse events.10,13
According to the results of clinical trials, roxadustat has a half-life
of 13 h,18 and can be administered three times a week to obtain
minimum necessary stabilization of HIF and thereby, a reduced
likelihood of adverse effects, while securing the appropriate
amount of EPO production for the correction of renal anemia. A
once-daily dosing regimen was set for daprodustat (half-life: 2.7
h)19 and vadadustat (4.5 h).12 We believe that a once-daily dosage
regimen would be the most suitable for an orally administered
drug, to ensure adequate compliance, and therefore, selected a
clinical candidate with a predicted half-life in humans of approxi-
mately 2–5 h.
Based on the above, we conducted further search aimed at dis-
covery of compounds with a predicted half-life in humans of 2–5 h
setting up compound 1 as the lead. Following screening for PHD2
enzyme inhibition, we conducted
a metabolic stability test
in vitro, a pharmacokinetic study in rats, and an EPO induction test
in mice. As a result, we successfully produced TP0463518 (42) as a
clinical candidate with a predicted half-life in humans of 1.3–5.6 h,
which induced EPO production in rodents.
The synthetic routes of compound 1 and its derivatives 24–42
are summarized in Schemes 1 and 2. Secondary amines 4–7 were
prepared by reductive amination from b-amino ester 2a-d and
aldehyde 3a (Scheme 1-A). When b-alanine ethyl ester hydrochlo-
ride (2e) was used, triethylamine was added to obtain amines 8–23
(Scheme 1-B and C). Secondary amines 4–23 were acylated by
ethyl malonyl chloride, cyclized by the Dieckmann reaction, con-
verted to glycinamide by ester-amide exchange, and finally depro-
tected under acidic conditions to obtain compounds 1 and 24–42.
Compounds that were difficult to solidify were converted to their
sodium salts (Scheme 2).
PHD subtypes 1 to 3 have been identified. Search for inhibitors
of PHD2 by high-throughput screening (HTS)20 and preparation of
co-crystals with ligands21 had been conducted. Known PHD inhibi-
tors are classified as glycinamide derivatives and derivatives of
other compounds. The former have a common structure (2-oxoglu-
talic acid mimic), shown in red in Fig. 2. X-ray crystallographic
analysis of the structure of a PHD2-ligand complex has revealed
ionic interaction of glycine carboxylate with an Arg 383 residue,
bidentate coordination of amide carbonyl and the donor atom
adjoining it to iron, and hydrogen bond formation between a
highly acidic hydroxyl group conjugated with amide and Tyr 303.
Fig. 2. PHD inhibitor motif and lead compound 1.
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M. Hamada et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
3
Scheme 1. (a) NaBH(OAc)3, AcOH, CHCl3, rt. (a0) NaBH(OAc)3, AcOH, Et3N, CHCl3, rt.
Compound 1 exerted moderate PHD2-inhibitory activity (52%
inhibition at 1 M). Increase of the serum EPO (2323 pg/mL) was
which the methyl group differed in position from that in 25, was
equivalent in profile to the parent compound. In addition, non-
substituted compound 27 also exerted potent enzyme-inhibitory
activity. The lipophilicity of this compound was very low (CLogP
= 2.65) as compared to that of 1 (CLogP = 4.65). The serum protein
binding was decreased to 98.9% in humans and 99.3% in rats. How-
ever, unexpectedly, the metabolic rate of compound 27 in the rat
hepatocytes was high as 34.4%.
It was found that a bulky substituent on the dihydropyridinone
ring had a negative effect on the interaction of the compound with
the PHD2 enzyme, and that compounds with less bulky sub-
stituents showed enhanced PHD2-inhibitory activity, as compared
to 1. In addition, the metabolic rate in rat hepatocytes was also
reduced with a decrease in the lipophilicity, except for compound
27, which showed a different tendency. Metabolite analysis of
compound 27 revealed that the metabolic site differs from 1, and
l
detected in mice, but not in rats, at 6 h after oral administration
of this compound at the dose of 100 mg/kg. We found that the
unbound concentration was insufficient, because the serum pro-
tein binding was ꢀ99.4% in both humans and rats, and the rate
of metabolism in rat hepatocytes was 31.3% (Table 1). Analysis of
the metabolites by liquid chromatography-tandem mass spec-
trometry (LC-MS/MS) revealed that the cyclohexane ring or adja-
cent carbon atom moiety underwent oxidative metabolism.
Therefore, we attempted to resolve these problems by changing
the spirocyclic structure and reducing the lipophilicity. Com-
pounds 24 and 25, with a reduced substituent volume and
improved lipophilicity, showed high enzyme-inhibitory activities;
while their metabolism in rat hepatocytes was also suppressed,
they still showed high serum protein binding. Compound 26, in
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M. Hamada et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
Following evaluation of the PHD2-inhibitory activity, the
efficacy (measurement of the serum level of EPO at 6 h after
single oral administration at a dose of 40 mg/kg) and/or phar-
macokinetics (PK) (following single intravenous administration)
of the compound in inducing EPO production was evaluated
and the results are shown in Table 2. While mice were used
for the in vivo screening, rats were used for the PK evaluation
to predict the half-life in humans. Compound 28, in which the
terminal phenyl ring of compound 27 was replaced with a
methyl group, again showed reduced inhibitory activity. Com-
pound 29, with a 4-chlorobenzyl side chain, showed moderate
PHD2-inhibitory activity.
A trifluoromethyl substituent was
used for the search of appropriate substitution positions for
the benzyl group. Ortho- (30) and meta-substitution of benzyl
groups (31) led to a reduction of the PHD2-inhibitory activity.
Para-substitution (32) yielded inhibitory activity similar to that
of compound 29 and stronger than that of compounds 30 and
31. The effective half-life23 of compound 32 in rat was 4.9 h
and its predicted half-life in humans was 18 h. Since it was
much greater than the targeted value (2–5 h),
a search for
appropriate substituents was continued to obtain improved
inhibitory activity and optimal half-life in humans. 4-(Trifluo-
romethoxy)benzylated compound 33 had equal activity to 32,
with an effective half-life in rats of 2.8 h. 4-Cyclopropyloxyben-
zyl compound 34 showed an effective half-life of 0.55 h in rats.
As the methylene chain was elongated (35 to 36), the enzyme-
inhibitory activity improved, and both compounds promoted
the production of EPO in mice (6258 and 8163 pg/mL). The
effective half-life in rats was 1.4 h for compound 35, and
0.46 h for compound 36. Highly lipophilic compound 37 carry-
ing
a 4-(4-methylphenoxy)benzyl side chain showed strong
inhibitory activity, however, its efficacy of inducing EPO pro-
duction was low (serum EPO at 6 h, 4441 pg/mL) and its
half-life in rats was 0.52 h. Although the enzyme-inhibitory
activity was enhanced by conversions up to this point, the
lipophilicity also increased. Therefore, we attempted to reduce
the lipophilicity by converting the side-chain phenyl ring to
a pyridine ring based on compounds 36 and 37, which showed
strong enzyme-inhibitory activities. Compounds 38 and 39, in
which the benzene ring in the side chain was switched to a
2-pyridine ring, showed maintained enzyme-inhibitory activity,
their EPO-inducing efficacy in mice decreased. Compounds 40
and 41, with the nitrogen atom at another position, kept
PHD2-inhibitory activity and EPO-inducing efficacy in mice
and showed low lipophilicity as compared with compounds
36 and 37. The effective half-lives of compounds 40 and 41
in rats were 0.42 h and 0.72 h, about the same as those of
compounds 36 and 37. Based on the results of matched molec-
ular pair analysis that the half-life was extended,24 compound
42, in which the terminal methyl group of compound 41 was
substituted with chlorine, was synthesized. This compound
induced strong EPO production in mice (8371 pg/mL), and its
effective half-life was 1.5 h in rats.
Compound 42 showed good human PHD2-inhibitory activity
and good EPO-inducing efficacy in mice. IC50 values for human
and rat PHD2, the EPO-inducing efficacy determined in rats at
8 h after oral administration, the plasma protein binding, the
metabolic rate in the hepatocytes, the pharmacokinetics in rats
and dogs, and the predicted half-life of compound 42 in
humans were investigated, and the results are summarized in
Table 3. Compound 42 powerfully inhibited both human and
rat PHD2 (IC50: 13 nM and 18 nM, respectively). The serum level
of EPO in rats at 8 h after oral administration of the compound
at 40 mg/kg was 3003 pg/mL, sufficient for correcting anemia.
The plasma protein bindings were 99.1% in humans and 98.9%
in rats and dogs. The metabolism rates in the hepatocytes were
Scheme 2. (a) ethyl malonyl chloride, Et3N, EtOAc, rt. (b) NaOEt, EtOH, rt. (c)
glycine tert-butyl ester hydrochloride, 1,2-dimethoxyethane, reflux. (d) 4 N HCl/
Dox, rt. (e) 1 N aq. NaOH, acetone, rt.
a compound in which the biphenyl moiety was hydroxylated was
presumed to be the main metabolite. Although the metabolic rate
of 27 in rat hepatocytes was equal to 1, the presumed metabolic
site was a side chain, which could be resolved by conversion of
the side chain structure. In addition, due to its simple synthesis
and high lipophilic efficiency, compound 27 was set as an
advanced lead compound, and structural conversion of (1,10-biphe-
nyl)-4-ylmethyl side chain moiety was undertaken. The results are
summarized in Table 2.
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M. Hamada et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
5
Table 1
Effect of central-core substitutions on PHD2 inhibition, serum protein binding, and rat hepatocyte metabolism.
Compd
R1
R2
R3
PHD2
Serum protein binding (%)
Rat Hep metabolism (1 h, %)
CLogP
inhibitiona (%)
Human
Rat
1
A(CH2)5A
A(CH2)3A
Me
H
H
H
H
H
Me
H
52
88
93
95
94
>99.4
99.5
>99.4
>99.5
98.9
>99.4
>99.4
>99.4
>99.5
99.3
31.3
13.0
3.8
6.0
34.4
4.65
3.53
3.17
3.17
2.65
24
25
26
27
H
H
H
a
Concentration of compound: 1 lM.
Table 2
Side chain conversion of 27.
hPHD2 inhibitiona (%)
Mouse EPOb (pg/mL)
Rat iv t1/2eff (h)
CLogP
c
Compd
R
R4
28
29
30
31
32
33
34
35
36
37
4-Me
4-Cl
2-CF3
3-CF3
4-CF3
4-F3CO
4-(c-Pr)O
4-(c-Pr)CH2O
4-(c-Pr)CH2CH2O
4-(p-Tol)O
77
88
70
67
86
85
83
91
–
–
–
–
–
–
–
6258
8163
4441
–
–
–
–
4.9
2.8
0.55
1.4
0.46
0.52
1.27
1.48
1.65
1.65
1.65
1.79
1.27
1.66
2.19
3.36
97
102 (49)d
38
39
(c-Pr)CH2CH2O
(p-Tol)O
82
95 (69)
471
1488
–
–
1.19
1.87
d
40
41
42
(c-Pr)CH2CH2O
(p-Tol)O
(p-ClC6H4)O
90
7530
3497
8371
0.42
0.72
1.5
1.59
1.87
2.08
104 (39)d
104 (13)d
e
a
b
c
Concentration of each compound: 1
40 mg/kg, po.
Effective half-life.
The IC50 value (nM) are shown in brackets.
Sodium salt.
lM.
d
e
5.7% in humans, 0.9% in rats, and ꢁ0.3% in dogs. The urinary
excretion ratios of the unchanged drug were 0.1% in rats and
15.2% in dogs. The bioavailability of compound 42 was 52.8–
82.8%. The half-life in humans was predicted as 1.3–5.6 h by
analysis of the pharmacokinetic parameters in rats and dogs.25
From the above results, we determined compound 42 as a clin-
ical candidate and tested its EPO-inducing efficacy in an animal
model (5/6th nephrectomized spontaneously hypertensive rat)
and in healthy rhesus monkeys after oral administration. These
results will be published shortly.
In conclusion, we developed a new class of PHD2 inhibitor
drugs, structurally characterized by a 4-hydroxy-2-oxo-1,2,5,6-
tetrahydropyridine core, based on X-ray crystallographic
analysis of the PHD2-ligand complex and known structural
information on the ligands. To avoid adverse effects due to
excessive stabilization of HIF, our study was directed towards
developing compounds with a predicted half-life in humans of
2–5 h. Eventually, we identified compound 42 as
a clinical
candidate. A phase 1 clinical trial of this compound has been
conducted in Japan.
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6
M. Hamada et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
Table 3
4. Gouva C, Nikolopoulos P, Ioannidis JP, Siamopoulos KC. Treating anemia early in
renal failure patients slows the decline of renal function: randomized
controlled trial. Kidney Int. 2004;66:753–760.
5. Tsubakihara Y, Gejyo F, Nishi S, et al. High target hemoglobin with
erythropoiesis-stimulating agents has advantages in the renal function of
non-dialysis chronic kidney disease patients. Ther Apher Dial. 2012;16:
529–540.
6. Schödel J, Oikonomopoulos S, Ragoussis J, et al. High-resolution genome-wide
mapping of HIF-binding sites by ChIP-seq. Blood. 2011;117:e207–e217.
7. Wengerh RH. Cellular adaptation to hypoxia: O2-sensing protein hydroxylases,
hypoxia-inducible transcription factors, and O2-regulated gene expression.
FASEB J. 2002;16:1151–1162.
Profile of 42.a
a
Pharmacology
Human/rat PHD2 IC50 (nM)
Rat serum EPO (40 mg/kg, po) (pg/mL)
13 / 18
3003
Pharmacokinetics
(in vitro)
Plasma protein binding (%)
Hep metabolized 4 h (%)
Human
99.1
5.7
Rat
98.9
0.9
Dog
98.9
ꢁ0.3
Dog
1
197
231
4.7
15.2
5
6980
0.75
3.5
52.8
1.3
(in vivo)
iv
Rat
1
437
904
3.1
8. Jaakkola P, Mole DR, Tian YM, et al. Targeting of HIF-a to the von Hippel-Lindau
ubiquitylation complex by O2-regulated prolyl hydroxylation. Science.
2001;292:468–472.
Dose (mg/kg)
CLtot (mL/h/kg)
Vdss (mL/kg)
t1/2 (h)
9. Ivan M, Kondo K, Yang H, et al. HIFa targeted for VHL-mediated destruction by
proline hydroxylation: implications for O2 sensing. Science. 2001;292:464–468.
10. Rabinowitz MH. Inhibition of hypoxia-inducible factor prolyl hydroxylase
domain oxygen sensors: tricking the body into mounting orchestrated survival
and repair responses. J Med Chem. 2013;56:9369–9402.
11. Higashijima Y, Tanaka T, Nangaku M. Structure-based drug design for hypoxia-
inducible factor prolyl-hydroxylase inhibitors and its therapeutic potential for
the treatment of erythropoiesis-stimulating agent-resistant anemia: raising
expectations for exploratory clinical trials. Expert Opin Drug Discov.
2013;8:965–976.
12. Gupta N, Wish JB. Hypoxia-inducible factor prolyl hydroxylase inhibitors: a
potential new treatment for anemia in patients with CKD. Am J Kidney Dis.
2017;69:815–826.
13. Maxwell PH, Eckardt KU. HIF prolyl hydroxylase inhibitors for the treatment of
renal anaemia and beyond. Nat Rev Nephrol. 2016;12:157–168.
14. (a) Ogoshi Y, Matsui T, Mitani I, et al. Discovery of JTZ-951: a HIF prolyl
hydroxylase inhibitor for the treatment of renal anemia. ACS Med Chem Lett.
2017;8:1320–1325;
UERb (%)
0.1
10
po
Dose (mg/kg)
Cmax (ng/mL)
tmax (h)
t1/2 (h)
BA (%)
10,700
0.25
2.3
82.8
5.6
Predicted human t1/2 (h)
a
The free form of compound 42 was used for both the in vitro pharmacology and
in vivo pharmacokinetics studies. On the other hand, the sodium salt of compound
42 was used for the in vivo pharmacology and in vitro pharmacokinetics studies.
b
Urinary excretion ratio of the unchanged drug.
Acknowledgement
(b) Debenham JS, Madsen-Duggan C, Clements MJ, et al. Discovery of N-[Bis(4-
methoxyphenyl)methyl]-4-hydroxy-2-(pyridazin-3-yl)pyrimidine-5-carboxamide
(MK-8617), an orally active pan-inhibitor of hypoxia-inducible factor prolyl
We thank Fumihito Ushiyama, Fumiyasu Shiozawa, Kenichi
Kawabe, and Yuki Shimizu-Iwata for the contribution to the syn-
thesis of the compounds, and Katsumasa Otake for collecting the
pharmacokinetic data. We also thank Yoshiki Fukasawa, Hiroshi
Kawamoto, Hiroo Miyagawa, and Susumu Yamanobe for their help
in preparing this manuscript.
hydroxylase 1–3 (HIF PHD1-3) for the treatment of anemia.
2016;59:11039–11049.
J Med Chem.
15. Kidney Disease: Improving Global Outcomes (KDIGO) Anemia Work Group,
Brimble KS. KDIGO clinical practice guideline for anemia in chronic kidney
disease. Kidney Int Suppl. 2012;2:279–335.
16. Lau JH, Gangji AS, Rabbat CG, Brimble KS. Impact of hemoglobin and
erythropoietin dose changes on mortality: a secondary analysis of results
from
a randomized anemia management trial. Nephrol Dial Transplant.
Declarations of interest
2010;25:4002–4009.
17. Bradbury BD, Wang O, Critchlow CW, et al. Exploring relative mortality and
Epoetin Alfa dose among hemodialysis patients. Am
2008;51:62–70.
J
Kidney Dis.
None.
18. Groenendaal-van de Meent D, Adel M, Noukens J, et al. Effect of moderate
hepatic impairment on the pharmacokinetics and pharmacodynamics of
Roxadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor. Clin
Drug Invest. 2016;36:743–751.
Funding
19. Johnson BM, Stier BA, Caltabiano S. Effect of food and gemfibrozil on the
pharmacokinetics of the novel prolyl hydroxylase inhibitor GSK1278863. Clin
Pharmacol Drug Dev. 2014;3:109–117.
This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.
20. Hewitson KS, Schofield CJ, Ratcliffe PJ. Hypoxia-Inducible factor prolyl-
hydroxylase: purification and assays of PHD2. Methods Enzymol.
2007;435:25–42.
A. Supplementary data
21. McDonough MA, Li V, Flashman E. Cellular oxygen sensing: crystal structure of
hypoxia-inducible factor prolyl hydroxylase (PHD2). Proc Natl Acad Sci USA.
2006;103:9814–9819.
Supplementary data associated with this article can be found, in
the online version, at https://doi.org/10.1016/j.bmcl.2018.04.039.
22. The crystal data registered on PDB (code: 2HBT) was used as docking template.
23. Effective half-life is calculated using following equation: t1/2eff = Vdss/CLtot
ln2.
ꢂ
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Please cite this article in press as: Hamada M., et al. Bioorg. Med. Chem. Lett. (2018), https://doi.org/10.1016/j.bmcl.2018.04.039