Discovery of JTZ-951: A HIF Prolyl Hydroxylase Inhibitor for the Treatment of Renal Anemia

Article abstract of DOI:10.1021/acsmedchemlett.7b00404

Inhibition of hypoxia inducible factor prolyl hydroxylase (PHD) represents a promising strategy for the discovery of a next generation treatment for renal anemia. We identified several 5,6-fused ring systems as novel scaffolds of the PHD inhibitor on the basis of pharmacophore analysis. In particular, triazolopyridine derivatives showed potent PHD2 inhibitory activities. Examination of the predominance of the triazolopyridines in potency by electrostatic calculations suggested favorable π-π stacking interactions with Tyr310. Lead optimization to improve the efficacy of erythropoietin release in cells and in vivo by improving cell permeability led to the discovery of JTZ-951 (compound 14), with a 5-phenethyl substituent on the triazolopyridine group, which increased hemoglobin levels with daily oral dosing in rats. Compound 14 was rapidly absorbed after oral administration and disappeared shortly thereafter, which could be advantageous in terms of safety. Compound 14 was selected as a clinical candidate.

Full text of DOI:10.1021/acsmedchemlett.7b00404

Letter
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Cite This: ACS Med. Chem. Lett. XXXX, XXX, XXX-XXX
Discovery of JTZ-951: A HIF Prolyl Hydroxylase Inhibitor for the
Treatment of Renal Anemia
Yosuke Ogoshi,*,† Takuya Matsui,†,# Ikuo Mitani,† Masahiro Yokota,† Masakazu Terashita,†
Dai Motoda,† Kazuhito Ueyama,† Takahiro Hotta,† Takashi Ito,† Yasunori Hase,† Kenji Fukui,‡
Katsuya Deai,‡ Hiromi Yoshiuchi,‡ Soichiro Ito,§ and Hiroyuki Abe*,†
‡
§
†Chemical Research Laboratories, Biological Pharmacological Research Laboratories, Drug Metabolism & Pharmacokinetics
Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka
569-1125, Japan
S
* Supporting Information
ABSTRACT: Inhibition of hypoxia inducible factor prolyl hydroxylase (PHD) represents a promising strategy for the discovery
of a next generation treatment for renal anemia. We identified several 5,6-fused ring systems as novel scaffolds of the PHD
inhibitor on the basis of pharmacophore analysis. In particular, triazolopyridine derivatives showed potent PHD2 inhibitory
activities. Examination of the predominance of the triazolopyridines in potency by electrostatic calculations suggested favorable
π−π stacking interactions with Tyr310. Lead optimization to improve the efficacy of erythropoietin release in cells and in vivo by
improving cell permeability led to the discovery of JTZ-951 (compound 14), with a 5-phenethyl substituent on the
triazolopyridine group, which increased hemoglobin levels with daily oral dosing in rats. Compound 14 was rapidly absorbed
after oral administration and disappeared shortly thereafter, which could be advantageous in terms of safety. Compound 14 was
selected as a clinical candidate.
KEYWORDS: JTZ-951, PHD inhibitors, prolyl hydroxylase inhibitors, hypoxia inducible factor, HIF, erythropoietin, EPO, anemia
enal anemia occurs early in the development of chronic
matrix metabolism, glucose metabolism, cell proliferation, and
Rkidney disease (CKD), and the prevalence of anemia apoptosis.7 Levels of HIF are regulated metabolically via
hydroxylation of HIFα at a proline residue by the prolyl
hydroxylase (PHD) having three isoforms (PHD1−3).8 The
PHD activity is dependent on intracellular oxygen concen-
trations, which means hydroxylation of HIFα by PHD is
suppressed in the hypoxic state, resulting in stabilization of
HIFα and adaptation to hypoxia.5−8 These mechanisms suggest
that PHD inhibitors may increase internal EPO levels as a result
of HIF stabilization and could serve as alternatives to ESAs. In
fact, a PHD inhibitor FG-2216 was reported to increase the
EPO levels in patients on hemodialysis.9 Currently, several
compounds, including FG-4592 (roxadustat) and JTZ-951
(compound 14), are in clinical trials for renal anemia.6,10 We
increases as the disease progresses. The primary cause is the
depression of erythropoietin (EPO) production in the kidney
associated with the kidney disorder.1 Current standard
treatment for renal anemia is parenteral administration of
erythropoiesis stimulating agents (ESAs) such as recombinant
human erythropoietin (rhEPO), darbepoetin alfa, and epoetin
beta pegol. Whereas ESAs have improved the quality of life in
CKD patients, there still remain several problems to be
improved, which include matters related to injection and
adverse effects.2−4 Therefore, the development of small
molecule alternatives to ESAs is highly anticipated.5,6
Hypoxia inducible factor (HIF), composed of an oxygen-
regulated α subunit (HIFα) and a constitutively expressed β
subunit, is a key transcription factor that plays a central role in
response to hypoxia. HIF induces various genes related to
erythropoiesis including EPO, angiogenesis, vascular tone,
Received: October 6, 2017
Accepted: November 20, 2017
Published: November 20, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acsmedchemlett.7b00404
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Letter
started our PHD inhibitor program from exploration of novel
scaffolds and performed lead optimization, guided by the
PHD2 enzyme assay and the EPO release assay from Hep3B
cells. In this letter, we report our research efforts, which led to
the discovery of compound 14.
Table 1. SAR of 5,6-Fused Ring Systems
Active site inhibitors of PHD are known to have three
common pharmacophores, which consist of a bidentate
coordination site to an iron atom, a carboxylic acid forming a
salt bridge to the Arg383 side chain, and a hydrogen bond
acceptor for the phenolic hydroxyl of Tyr303. Several
compounds including FG-2216 have an additional interaction
with Tyr310 by a π−π stacking (Figure 1a).11,12 On the basis of
a
Mean value determined from four replicates. Standard deviations are
b
reported in the Supporting Information. The concentration showing
50% increase in EPO release from Hep3B cells relative to the positive
c
control. See the Supporting Information for assay details. Apparent
d
e
f
permeability coefficient. HCl salt. Value reported in ref 15. Value
reported in ref 16.
studies suggested that only one binding mode I was accessible.
Coordination of the iron ion is achieved through the azole
nitrogen atom, which allows a π−π stacking between the fused
pyridine rings and the phenol ring of Tyr310 (I in Figure 1b).
However, the azole ring will make steric clashes with Tyr303 in
another binding mode (II in Figure 1b). Then, we analyzed the
electrostatic potential maps of the 5,6-fused rings in 1−5.
Triazolopyridines had electron-deficient fused pyridine rings
compared to imidazopyridine and pyrazolopyridine (Figure 1c,
region within the green box). In general, π−π stacking is
preferentially located between an electron-deficient ring and an
electron-rich one.14 Therefore, triazolopyridines are considered
more favorable as a stacking counterpart with the electron-rich
phenol of tyrosine, assuming that the difference in the
electronic property of the fused pyridines has an impact upon
the PHD2 inhibitory activity.
Although triazolopyridine derivatives 3−5 exhibited potent
PHD2 inhibitory activities, these compounds failed to stimulate
EPO release from Hep3B cells at concentrations up to 30 μM.
We assumed that this lack of effect was due to the poor cell
permeability (Papp) of the compounds and that increasing the
lipophilicity could stimulate EPO release. Since the triazolopyr-
idine derivatives 3−5 had high LLEs (5.1−5.6), we thought
there would be sufficient space to introduce appropriate
Figure 1. (a) Crystal structure of PHD2 in complex with FG-2216 and
a representative pharmacophore common to typical PHD inhibitors
(PDB code 2HBT). (b) Two binding models I and II of compound 4
bound to the active site of PHD2. (c) Electrostatic potential map of
5,6-fused ring systems. Positive, negative, and neutral charges are
colored in blue, red, and white, respectively. The pyridine moiety is
outlined by the green box.
this pharmacophore model, many scaffold hopping efforts have
been made and reviewed.12,13 We synthesized various scaffolds
and tested them. Several compounds showed potent PHD
inhibitory activities but failed to show adequate activity in the
cell or in vivo. However, with sustained efforts of exploration,
we finally identified 5,6-fused ring systems 1−5 as promising
lead compounds (Table 1). The imidazopyridine derivative 1
and the pyrazolopyridine derivative 2 showed PHD2 inhibitory
activity comparable to FG-2216, and moreover, the triazolopyr-
idine derivatives 3−5 were more potent than 1 and 2. To
discuss the differences in potency, we first analyzed the binding
modes by modeling studies. Although there are two possible
binding modes in which the 5,6-fused ring is flipped relative to
the amide carbonyl (I and II in Figure 1b), the modeling
B
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Table 2. SAR of Scaffold A and Scaffold B
a
b
Mean value determined from four replicates. Standard deviations are reported in the Supporting Information. The concentration showing 50%
c
increase in EPO release from Hep3B cells relative to the positive control. See the Supporting Information for assay details. Apparent permeability
coefficient. Mean value determined from three replicates. Standard deviations are reported in the Supporting Information. Free form.
d
e
lipophilic substituents.17 We selected compounds 4 and 5 as
lead compounds, excluding 3, which had extremely low
permeability, and conducted lead optimization (Table 2).
Initially, various alkyl chains were introduced to compound 4
(scaffold A) at the R1 position to verify the expected
improvement on the cell permeability and the activity in
cells. The introduction of n-propyl (6), n-butyl (7), and n-
pentyl groups (8) had no influence on PHD2 inhibitory
activity. Cell permeability (Papp) was improved in these
compounds along with ClogP as expected. Encouragingly,
compounds 6, 7, and 8 stimulated EPO release from Hep3B
cells with EC50 values equivalent to or more potent than that of
FG-4592. Moreover, compounds 7 and 8 elicited significant
increases of EPO levels in mice (plasma EPO > 2000 pg/mL at
8 h after oral administration at a dose of 10 mg/kg). We next
synthesized compounds 9 and 10 with substituents at the R2
position. These compounds showed weak PHD2 inhibitory
activity and were not effective in mice at 10 mg/kg. These
results indicated that the spatial tolerance around the R2
position is narrow. Therefore, we focused the introduction of
C
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lipophilic substituents on the R1 position. We investigated
several different types of lipophilic substitution at the R1
position (11−15). The substituents having a phenyl ring
showed higher PHD2 inhibitory activities (compounds 12−
15), while all the compounds exhibited similar potency in cells
as obtained with 7 and 8. In particular, compounds 13 and 14
showed significant EPO production activities in mice.
Introduction of a methyl group at the R3 position (compound
16) resulted in a large decrease in PHD2 inhibitory activity.
Having these results, another lead compound 5 (scaffold B) was
examined. Introduction of the same substituents as compounds
11−14 gave similar results both in the enzyme assay and the
cell assay (compounds 17−20). However, they were not active
in mice at 10 mg/kg, suggesting that scaffold A was superior to
scaffold B in terms of EPO production in mice.
The compounds 7, 8, 13, and 14, which significantly
increased plasma EPO levels in mice, were then tested in rats.
They significantly stimulated EPO production in rats as well.
Unfortunately, a slight anorectic effect was observed in rats
orally administered 100 mg/kg of compounds 8 and 13.
However, compounds 7 and 14 did not show anorectic effects.
These results encouraged us to advance compounds 7 and 14
for further investigation.
The effect of compounds 7 and 14 on hemoglobin levels in
rats was examined. Oral dosing of compound 14 at 1 and 3 mg/
kg daily resulted in dose-dependent increases of hemoglobin
levels (Figure 2). No increase in hemoglobin levels was
observed at 3 mg/kg dose of compound 7, but administration
at 10 mg/kg increased these levels.
Figure 3. (a) Pharmacokinetic curves of 14 in rats. Each data point
represents the mean SD (n = 3). (b) PK parameters of 14 in rats.
(c) PK related parameters of 14.
The synthetic route of compound 14 is shown in Scheme 1.
tert-Butyl esterification of 2,4-dichloronicotinic acid 21 and
subsequent regioselective nucleophilic aromatic substitution
with benzyl alcohol gave 22. After displacement of chlorine
with hydrazine, sequential cyclization with ortho-ester afforded
the [1,2,4]triazolo[4,3-a]pyridine derivative 23. Dimroth
rearrangement proceeded smoothly in the presence of
morpholine in refluxing AcOEt to give the [1,2,4]triazolo[1,5-
a]pyridine derivative 24, which was converted by regioselective
iodination into the coupling precursor 25. Sonogashira
coupling with phenylacetylene and removal of the tert-butyl
group by treating with TFA provided the carboxylic acid 26.
Amide formation with glycine ethyl ester followed by
hydrogenation and hydrolysis of the ester afforded compound
14.
In conclusion, following the identification of novel
triazolopyridine derivatives as potent scaffolds of PHD2
inhibitor, our lead optimization to improve cell permeability
led to the discovery of compound 14 (JTZ-951), a potent and
orally active PHD inhibitor. Compound 14 at 1 and 3 mg/kg
dose-dependently increased hemoglobin levels with daily oral
dosing in rats. The short-acting PK profile of compound 14 is
expected to be advantageous in terms of safety. Compound 14
has been advanced to phase II clinical trials for renal anemia.
Figure 2. Changes in hemoglobin levels following 29-day once-daily
dosing of 7 (magenta) and 14 (green) in rats. Standard deviations are
reported in the Supporting Information.
In terms of pharmacokinetic (PK) profiles, compound 14
was rapidly absorbed after oral administration in rats and
disappeared shortly thereafter (Figure 3a,b). As Vachal and
others have mentioned, the short-acting characteristics could be
beneficial in reducing unpredictable adverse effects in light of
the HIF-PHD mechanism.18 Compound 14 also had excellent
solubility and metabolic stability (Figure 3c). In addition, it
showed neither CYP (IC50 > 100 μM; CYP3A4/5, CYP2C9,
CYP2D6, CYP1A2, CYP2A6, CYP2C19, CYP2C8, CYP2B6)
nor hERG (IC50 > 100 μM) inhibition. Having these results,
compound 14 was selected for a clinical candidate.
D
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a
Scheme 1. Synthesis of 14
ABBREVIATIONS
■
SD, standard deviation; BF3·Et2O, boron trifluoride diethyl
ether complex; p-TsOH·H2O, p-toluenesulfonic acid mono-
hydrate; LHMDS, lithium hexamethyldisilazan; MsOH, meth-
anesulfonic acid; EDC, 1-(3-(dimethylamino)propyl)-3-ethyl-
carbodiimide hydrochloride; HOBt, 1-hydroxybenzotriazole
monohydrate; TEA, triethylamine; CYP, cytochrome P450;
hERG, human ether-a-go-go-related gene
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a
Reagents and conditions: (a) tert-butyl 2,2,2-trichloroacetimidate,
BF3·Et2O, THF; (b) benzyl alcohol, NaH, DMF, 0 °C; (c) hydrazine
hydrate, 1,4-dioxane, 100 °C; (d) p-TsOH·H2O, trimethyl orthofor-
mate, 60 °C; (e) morpholine, AcOEt, reflux; (f) I2, LHMDS, THF,
−60 °C; (g) phenylacetylene, PdCl2(PPh3)2, CuI, TEA, toluene; (h)
MsOH, toluene−AcOEt; (i) glycine ethyl ester hydrochloride, EDC,
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ASSOCIATED CONTENT
■
S
* Supporting Information
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acsmedchem-
lett.7b00404.
Synthetic schemes, procedures, experimental data of all
compounds, assay procedures, and supporting tables with
standard deviation (PDF)
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Ratcliffe, P. J. C. elegans EGL-9 and Mammalian Homologs Define a
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AUTHOR INFORMATION
■
Corresponding Authors
*Phone: +81-72-681-9700. E-mail: yosuke.ogoshi@jt.com.
*Phone: +81-72-681-9700. E-mail: hiroyuki.abe@jt.com.
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Hydroxylases Increases Erythropoietin Production in ESRD. J. Am.
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Yosuke Ogoshi: 0000-0002-1440-6701
Present Address
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Randomized placebo-controlled dose-ranging and pharmacodynamics
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#Toxicology Research Laboratories Central Pharmaceutical,
Central Pharmaceutical Research Institute, Japan Tobacco Inc.,
23 Naganuki, Hadano, Kanagawa 257-0024, Japan.
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contributed to design and synthesis of JTZ-951. Y.H.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. Hisashi Shinkai and Dr. Susumu Kato for helpful
discussions. We are also grateful to Dr. Hisashi Kawasaki and
Dr. Hiromasa Hashimoto for suggestions on writing this letter.
E
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