Discovery of evocalcet, a next-generation calcium-sensing receptor agonist for the treatment of hyperparathyroidism

Article abstract of DOI:10.1016/j.bmcl.2018.04.055

The calcium-sensing receptor (CaSR) plays an important role in sensing extracellular calcium ions and regulating parathyroid hormone secretion by parathyroid gland cells, and the receptor is a suitable target for the treatment of hyperparathyroidism. Cinacalcet hydrochloride is a representative CaSR agonist which widely used for the hyperparathyroidism. However, it has several issues to clinical use, such as nausea/vomiting and strong inhibition of CYP2D6. We tried to improve these issues of cinacalcet for a new pharmaceutical agent as a preferable CaSR agonist. Optimization from cinacalcet resulted in the identification of pyrrolidine compounds and successfully led to the discovery of evocalcet as an oral allosteric CaSR agonist. Evocalcet, which exhibited highly favorable profiles such as CaSR agonistic activity and good DMPK profiles, will provide a novel therapeutic option for secondary hyperparathyroidism.

Full text of DOI:10.1016/j.bmcl.2018.04.055

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 evocalcet, a next-generation calcium-sensing receptor
agonist for the treatment of hyperparathyroidism
a
a
a
a
a
Hiroshi Miyazaki a, , Yousuke Ikeda , Osamu Sakurai , Tsutomu Miyake , Rie Tsubota , Jyunko Okabe ,
Masataka Kuroda a, Yutaka Hisada a, Tetsuya Yanagida a, Hikaru Yoneda a, Yukihito Tsukumo b,
Shin Tokunaga b, Takehisa Kawata b, Rikiya Ohashi a, Hajime Fukuda a, Koki Kojima a, Ayako Kannami a,
Takayuki Kifuji a, Naoya Sato a, Akiko Idei a, Taku Iguchi a, Tetsuya Sakairi a, Yasunori Moritani a
⇑
a Mitsubishi Tanabe Pharma Corporation, 1000, Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan
b Kyowa Hakko Kirin Co., Ltd., 1188, Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8731, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The calcium-sensing receptor (CaSR) plays an important role in sensing extracellular calcium ions and
regulating parathyroid hormone secretion by parathyroid gland cells, and the receptor is a suitable target
for the treatment of hyperparathyroidism. Cinacalcet hydrochloride is a representative CaSR agonist
which widely used for the hyperparathyroidism. However, it has several issues to clinical use, such as
nausea/vomiting and strong inhibition of CYP2D6. We tried to improve these issues of cinacalcet for a
new pharmaceutical agent as a preferable CaSR agonist. Optimization from cinacalcet resulted in the
identification of pyrrolidine compounds and successfully led to the discovery of evocalcet as an oral allos-
teric CaSR agonist. Evocalcet, which exhibited highly favorable profiles such as CaSR agonistic activity and
good DMPK profiles, will provide a novel therapeutic option for secondary hyperparathyroidism.
Ó 2018 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://
creativecommons.org/licenses/by/4.0/).
Received 26 March 2018
Revised 19 April 2018
Accepted 23 April 2018
Available online xxxx
Keywords:
Evocalcet
Calcium-sensing receptor (CaSR)
Allosteric calcium-sensing receptor agonist
Hyperparathyroidism
Cinacalcet
Secondary hyperparathyroidism (SHPT), which causes the
excessive production of parathyroid hormone (PTH) by the
parathyroid glands, is a common mineral and bone disorder in
patients with chronic kidney disease (CKD) and end-stage renal
disease (ESRD).1 In this disorder, high serum PTH levels induce
high-turnover bone disease and increase serum calcium and phos-
phate levels via efflux from the bone. This abnormity of calcium
and phosphate metabolism is associated with risks of fracture, vas-
cular calcification, and cardiovascular mortality.2–5
The calcium-sensing receptor (CaSR) is a class C G-protein cou-
pled receptor (GPCR) that senses extracellular calcium ions and
regulates PTH secretion by parathyroid gland cells.6 Cinacalcet
hydrochloride (1, Fig. 1), a calcimimetic agent which allosterically
activates CaSR, is widely used for the oral treatment of SHPT in
dialysis patients by decreasing the serum PTH, calcium and phos-
phate levels.7–14 In addition, cinacalcet can slow the progress of
cardiovascular calcification and reduce the risk of mortality.15–17
However, cinacalcet has several drawbacks such as adverse effects
on the gastrointestinal (GI) tract (e.g., nausea and vomiting)18 and
potential drug-drug interactions due to its strong inhibition of
cytochrome P450 2D6 (CYP2D6).19 In particular, these GI adverse
effects limit the dose of cinacalcet and result in poor compliance
or treatment discontinuation.20,21
As our initial drug discovery efforts targeting novel cal-
cimimetic agents without the drawbacks of cinacalcet, we started
an exploration of cinacalcet analogs. Efforts to improve its CaSR
agonistic activity, oral exposure, and CYP2D6 inhibition success-
fully led to the discovery of evocalcet (16). In this study, we dis-
close the structure–activity relationships (SARs) and findings of
evocalcet and its pyrrolidine derivatives.
Structural information of CYP2D6 from homology models
reveals that the characteristic features of CYP2D6 substrates are
a basic nitrogen and a planar hydrophobic area22, which might
explain the strong CYP2D6-inhibitor effects of cinacalcet (IC50
<
0.1 M). However, the basic nitrogen of cinacalcet in the center
l
position interacts with Glu837 of CaSR, and this nitrogen moiety
is essential for its agonistic activity, as will be described later.23
In the design of new drugs, a strategy of hindering the basic amine
surroundings was selected to weaken the affinity for CYP2D6 and
decrease CYP2D6 inhibition. As a result, a diisopropylamine-type
compound (i.e., pyrrolidine analog 2) exhibited moderate agonistic
efficacy toward human CaSR and reduced CYP2D6 inhibition
(Fig. 2, Table 1).
⇑
Corresponding author.
E-mail address: miyazaki.hiroshi@me.mt-pharma.co.jp (H. Miyazaki).
https://doi.org/10.1016/j.bmcl.2018.04.055
0960-894X/Ó 2018 The Authors. Published by Elsevier Ltd.
This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Please cite this article in press as: Miyazaki H., et al. Bioorg. Med. Chem. Lett. (2018), https://doi.org/10.1016/j.bmcl.2018.04.055

2
H. Miyazaki et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
Fig. 1. Cinacalcet hydrochloride (1).
Fig. 2. Drug design and the structure of 2.
The search for more attractive compounds focused on deriva-
tives of 2. Our design of CaSR agonists is summarized in Fig. 3,
and their synthesis, including that of 2, is depicted in Schemes 1
and 2. tert-Butyl 3-hydroxypyrrolidine-1-carboxylate was con-
verted to the di-tert-butoxycarbonyl (Boc)-protected compounds
S2 and S3 in a three-step reaction. Separation of diastereoisomers
S2 and S3 via silica gel chromatography followed by deprotection
of Boc gave S4 and S5. In the case of piperidine compounds, 1-ben-
zyloxycarbonyl-3-piperidone was converted to a diastereomeric
mixture of carbamoyl chloride compounds in two steps that were
separated via filtration and silica gel chromatography to give
diastereomers S7 and S8. Deprotection of the carbamoyl chloride
and the benzyloxycarbonyl (Z) group by water and hydrogenation,
respectively, afforded piperidines S9 and S10. Key intermediates
S4, S5, S9, and S10 were transformed into designed CaSR agonists
2–11, 13–15, and evocalcet (16) using palladium coupling reac-
tions with the corresponding aryl halide or some conventional
Fig. 3. Compound 2, its derivatives and evocalcet (16).
chemical conversions. Regarding the reactions of S4, S5, S9, and
S10 in Scheme 2, these compounds were specifically reacted at
the less hindered ring nitrogen atom. Compound 12 was synthe-
sized from 3-hydroxypiperidine and obtained via separation from
its diastereoisomer.
Table 1
Calcium-sensing receptor (CaSR) agonistic efficacies, inhibitory effects on parathyroid hormone (PTH) production in rat parathyroid cells, and DMPK profiles.
Compound
Human CaSR (Ca2+
)
Inhibition of rat PTH production
CYP2D6 inhibition (%)
CLint (lL/min/mg
protein)
EC50
(
lM)
IC50 (nM)
10
l
M
1
l
M
0.1
3.0
15.8
nt
l
M
Human
Rat
2
3
4
5
0.43
0.32
0.23
8.8
9.7
4.3
116
nt
nt
nt
nt
nt
60.0
61.2
nt
421
206
nt
302
270
nt
nt
nt
nt
nt
6
7
8
9
10
11
12
13
0.38
0.19
0.45
0.60
0.12
0.29
0.60
1.1
2.1
1.4
13.1
11.7
7.8
87.6
85.2
nt
78.7
82.6
87.5
88.4
62.5
14.1
86.4
nt
54.8
54.0
85.1
85.9
15.8
0.0
79.0
nt
4.4
662
370
171
84
nt
97
225
nt
197
312
68b
610
231
370
176
nt
92
442
nt
nt
79.8
14.1
92.5
nt
8.0
31.8
>100
0.91
0.47
30.8
14
15
0.050
0.017
0.093
30.7
75.3
3.4
nt
667
42
nt
a
Evocalcet (16)
-
34b
nt: not tested.
a
IC50 of evocalcet for CYP2D6 was higher than 50 mM.
nHCl salt data.
b
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H. Miyazaki et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
3
Scheme 1. Synthesis of key intermediates S4, S5, S9, and S10. Reagents and conditions: (a) Tf2O, i-Pr2NEt, CH2Cl2, ꢀ20 °C. Then, (R)-(+)-1-(1-naphthyl)ethylamine, ꢀ20 °C to
rt (S1 57%); (b) triphosgene, Et3N, CH2Cl2, ꢀ20 °C to 5 °C. Then, i-Pr2NEt, tert-butanol, 70 °C; (c) separation via silica gel chromatography (S2 31%, S3 33% in 2 steps); (d) HCl,
chloroform, 1,4-dioxane, rt (S4 > 94%, S5 > 94%); (e) (R)-(+)-1-(1-naphthyl)ethylamine, NaBH(OAc)3, acetic acid, CH2Cl2, rt (S6 79%); (f) triphosgene, Et3N, CH2Cl2, 0 °C to rt; (g)
separation via filtration and silica gel chromatography (S7 58%, S8 16% in 2 steps); (h) water, tetrahydrofuran, reflux; (i) H2, Pd/C, methanol, rt (S9 50% in 2 steps); (j) HCl,
ethyl acetate, methanol, rt (S10 31% in 3steps).
Scheme 2. Synthesis of 2–15 and evocalcet (16). Reagents and conditions: (a) aryl iodide or aryl bromide, palladium acetate, (rac)-BINAP, sodium tert-butoxide, toluene, 80 °C
or reflux; (b) HCl, ethyl acetate or 1,4-dioxane, rt; (c) tert-butyl 4-fluorobenzoate, potassium carbonate, DMSO, 130 °C; (d) HCl, 1,4-dioxane, 45 °C; (e) 2-aminoethanol, EDC
hydrochloride, HOBt, Et3N, DMF, rt; (f) 5-(4-bromophenyl)-2-(triphenylmethyl)–2H-tetrazole, Pd2(dba)3, (2-biphenyl)di-tert-butylphosphine, sodium tert-butoxide, toluene,
rt; (g) HCl, water, 1,4-dioxane, rt; (h) tert-butyl 4-bromobenzoate, palladium acetate, (rac)-BINAP, sodium tert-butoxide, toluene, reflux; (i) trifluoroacetic acid, rt. Then, HCl,
ethyl acetate or 1,4-dioxane, rt (2 23%, 3 21%, 4 44%, 5 34%, 6 20%, 7 55%, 8 29%, 9 21%, 10 19%, 11 40%, 13 26%, 14 69%, 15 69% in 2 steps); (j) 3-(trifluoromethoxy)
phenylboronic acid, copper acetate, Et3N, CH2Cl2, molecular sieve 4A, rt (S11 7%); (k) (COCl)2, DMSO, Et3N, CH2Cl2, ꢀ60 °C to rt (S12 was used in the next step without
purification); (l) (R)-(+)-1-(1-naphthyl)ethylamine, NaBH(OAc)3, acetic acid, CH2Cl2, rt. Then, separation of isomers; (m) HCl, ethyl acetate, rt (12 10% in 2 steps); (n) ethyl 4-
bromophenylacetate, Pd2(dba)3, (2-biphenyl)di-tert-butylphosphine, sodium tert-butoxide, toluene, rt (S13 63%); (o) aqueous sodium hydroxide solution, ethanol, rt
(evocalcet (16) 73%).
Biological evaluations of 3–15 and evocalcet are also presented
in Table 1. Small lipophilic substituents (m- or p-trifluoromethoxy
group) were introduced onto the phenyl ring at the first position of
pyrrolidine of 2, and these compounds, namely 3 and 4, displayed
nearly identical agonistic efficacy. Although 4 exhibited extremely
weak inhibitory activity against PTH production in rat parathyroid
cells for unclear reasons, 3 also displayed similar CYP2D6-inhibi-
tory activity to 2.
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H. Miyazaki et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
We hypothesized that compounds need to be highly specifically
Unfortunately, their metabolic stabilities in human liver micro-
somes were unsatisfactory. Evocalcet, in which an acetic acid
moiety was introduced, was finally found to exhibit excellent phar-
macological profiles (CaSR agonistic activity and inhibition of PTH
production) and good DMPK profiles (CYP2D6 inhibition and meta-
bolic stability).
exposed to the parathyroid glands to reduce the adverse effects of
cinacalcet on the GI tract. Lower exposure of drugs in the GI tract
and central nervous system may also be important. Therefore, we
introduced a hydrophilic substituent for the lipophilic substituents
of compounds 2–4 in order to improve not only CYP2D6 inhibition
but also other profiles such as bioavailability and metabolic stabil-
ity; however, 5, with a carboxylic acid group in the phenyl ring as a
representative hydrophilic group, was found to exhibit weaker
To deeply understand the binding interactions with CaSR,
evocalcet was docked into the molecular model generated via a
conventional homology modeling method and prepared using
mutagenesis data described in a previous report.23 As shown in
Fig. 4, the basic nitrogen of evocalcet in the center position inter-
acts with Glu837 of CaSR in almost the same modes as those of
cinacalcet and NPS 568, which have been established as CaSR ago-
nists.25 Based on this docking model, the naphthalene ring of evo-
calcet was oriented toward the inside of the receptor. Conversely,
its acetic acid moiety was oriented toward the wide outside space
of the receptor. The (S)-pyrrolidine moiety may allow the com-
pound take an appropriate conformation in the complex and orient
the substituents of its phenyl ring to the outside. As observed in
the SARs of (S)-pyrrolidines 8–11, 14, 15, and evocalcet, this wide
outside space of the receptor might be able to permit different
types of substituents such as lipophilic and hydrophilic groups to
be introduced into its phenyl ring without decreasing CaSR
efficacy. In addition, the outside space might enable the adjust-
ment of the physicochemical properties and DMPK profiles of
compounds.26
effects on CaSR (EC50 = 8.8 lM).
Next, we attempted to explore the influence of the pyrrolidine
ring of 2. We expected that ring expanded or stereoisomeric struc-
tures of 2 would create an appropriate conformation that allows
modified compounds to interact with CaSR and lead to improved
efficacy. Piperidine analogs 6 and 7 displayed slightly increased
CaSR potency and inhibition of rat PTH production, but they
appeared to have stronger CYP2D6-inhibitory effects, contrary to
our expectation. Moreover, (R)-piperidines 6 and 7 exhibited worse
metabolic stabilities in human liver microsomes than (R)-pyrrolidi-
nes 2 and 3. As a result of further research, the (R)-pyrrolidine tem-
plate was found to have better profiles than the (R)-piperidine
template. Conversely, stereoisomers 8 and 9 (S-isomers of 2 and
3, respectively) exhibited a slightly weaker CaSR agonistic effect
with strong CYP2D6-inhibitory activities. However, 10, in which
a trifluoromethoxy group was introduced at the para position of
the phenyl ring, proved to have better agonistic efficacy than its
R-isomer 4. In the case of (S)-pyrrolidine compounds, substituents
at the para position appeared to enhance CaSR agonistic potency.
Surprisingly, it was revealed that (S)-pyrrolidine 11, having a
hydrophilic carboxylic acid in the para position of its phenyl ring,
possessed good CaSR potency and strongly inhibited PTH produc-
tion. 11 displayed weak CYP2D6 inhibition and good metabolic sta-
bility in liver microsomes. These favorable DMPK profiles of 11
were speculated to be due to its hydrophilic group. The hydrophilic
carboxylic acid group not only deviated 11 from the characteristic
features in CYP2D6 substrates, but also made 11 metabolically
stable as noted in Pfizer’s data mining research.24 Whereas (S)-
piperidine analog 12 had moderate CaSR potency, 13 exhibited
no remarkable potency.
Moreover, the specific binding of [3H] evocalcet to CaSR was
determined in human CaSR-expressing and control cells.27 The
specific binding of [3H] evocalcet in human CaSR-expressing cells
was higher than that in control cells, suggesting that evocalcet
binds to CaSR (Fig. 5). The effect of NPS 568 on the binding of
[3H] evocalcet to CaSR was also assessed. NPS 568 was found to
compete with [3H] evocalcet for binding to CaSR with an IC50 of
9.47 ꢁ 10ꢀ8 mol/L (Fig. 6). These data were consistent with the
results of the aforementioned models, and evocalcet proved to be
an allosteric agonist like cinacalcet and NPS 568.
Evocalcet was further evaluated for its DMPK profiles. Regard-
ing CYP inhibition, which is one of the issues of cinacalcet, the
IC50 values of evocalcet for inhibition of the specific activities of
CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6,
CYP2E1, and CYP3A4/5 all exceeded 50 mM. No remarkable direct
CYP inhibition was observed. Next, PK studies of evocalcet in rats
and monkeys were performed. As shown in Table 2, evocalcet
exhibited preferable PK profiles with high bioavailability (rat:
84%, monkey: 56%). Conversely, the bioavailability of cinacalcet
in rats is known to be approximately 1–2%, and that of 11 was only
12%. Regarding this point, it can be said that evocalcet has desir-
able profiles as a next-generation CaSR agonist compared with 11.
Encouraged by these fundamental data on the (S)-pyrrolidine
templates, we next intensified our campaign in further optimizing
the para substituents of 11. An amide moiety, a tetrazole ring (as a
carboxylic acid bioisostere), and an acetic acid moiety were
introduced as hydrophilic groups. The para position of the phenyl
ring in (S)-pyrrolidine compounds proved to allow several types
of hydrophilic groups. As observed for 11, 14 and 15 were
revealed to possess strong CaSR agonistic effects, strong inhibition
of rat PTH production, and good CYP2D6 inhibition profiles.
Fig. 4. Complex models of evocalcet (16) and NPS 568 with CaSR (A: evocalcet, B: NPS 568).aaGlu837 is highlighted in stick style (A: left) and CPK style (A: right and B).
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H. Miyazaki et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
5
on the GI tract of evocalcet are most likely due to its high bioavail-
ability. In a phase 3 clinical trial of evocalcet in patients undergoing
hemodialysis, noninferiority was verified in terms of PTH suppres-
sion in comparison with cinacalcet. Moreover, the incidence of GI
adverse effects was reduced in the evocalcet group.29
In summary, we conducted a research program starting from
cinacalcet and identified pyrrolidine compound 11 as a promising
lead compound. Further efforts to optimize compounds having the
(S)-pyrrolidine moiety finally resulted in the discovery of evocal-
cet. Evocalcet displayed strong CaSR agonistic effects and excellent
PK profiles with no remarkable direct CYP inhibition. Evocalcet was
also superior to cinacalcet concerning higher potential in vivo and
less effects on GI tract symptoms. Evocalcet, a next-generation
allosteric CaSR agonist, will provide a novel therapeutic option
for SHPT.
Acknowledgments
Fig. 5. Specific binding of [3H] evocalcet (16) to CaSR.aaThe specific binding in
control (s) and human CaSR-expressing (d) cells was determined. Specific binding
radioactivity was calculated by the following equation: Specific binding radioac-
This study was supported by Mitsubishi Tanabe Pharma
Corporation and Kyowa Hakko Kirin – Japan Co., Ltd. under a
collaboration agreement.
tivity (dpm)
radioactivity.
= B0 – N, B0; Total bound radioactivity, N; Non-specific bound
A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at https://doi.org/10.1016/j.bmcl.2018.04.055.
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described the details in a previous report.28 Oral administration
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PTH secretion in a rat model of CKD induced via 5/6 nephrectomy.
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a
Please cite this article in press as: Miyazaki H., et al. Bioorg. Med. Chem. Lett. (2018), https://doi.org/10.1016/j.bmcl.2018.04.055