Expert Opinion on Therapeutic Patents

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T-type calcium channel blockers: a patent review

(2012–2018)

Ghilsoo Nam

To cite this article: Ghilsoo Nam (2018) T-type calcium channel blockers: a patent
review (2012–2018), Expert Opinion on Therapeutic Patents, 28:12, 883-901, DOI:
10.1080/13543776.2018.1541982

To link to this article: https://doi.org/10.1080/13543776.2018.1541982

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EXPERT OPINION ON THERAPEUTIC PATENTS
2018, VOL. 28, NO. 12, 883–901
https://doi.org/10.1080/13543776.2018.1541982

REVIEW

T-type calcium channel blockers: a patent review (2012–2018)

Ghilsoo Nam
Center for Neuro-Medicine, Brain Science Institute, Korea Institutes of Science and Technology (KIST), Seoul, Republic of Korea; Division of Bio-
Medical Science, KIST School, Korea University of Science and Technology Seoul, Seoul, Republic of Korea

ABSTRACT ARTICLE HISTORY

Introduction: T-type calcium channels are attractive targets for potential treatment of epilepsy inflam- Received 10 September
matory or neuropathic pain, insomnia, Parkinson’s disease, and cancer. Three isoforms having different 2018
biophysical functions are expressed in peripheral and central nerve. Since the withdrawal of mibefradil, Accepted 25 October 2018
the first compound marketed for selective T-type calcium channel blockade, extensive efforts have been KEYWORDS
made to identify more selective T-type calcium channel blockers. CNS-related disease;
Areas covered: This review covers the 43 patents describing ‘organic small molecules as T-type calcium epilepsy; neuropathic pain;
channel blockers’-published since 2012. The most recent similar patent review was published in 2011. selective T-type calcium
Information from a recent review article and relevant research papers has been included, as well as channel blocker
biological data and clinical trial results where available.
Expert opinion: Triazinone derivatives, carbazole compounds, and aryl triazole/imidazole amide deri-
vatives display potent blockade activity α1H, α1G, and pan T-type calcium channel subtypes, respec-
tively, though the specificity of the letter is still unsatisfactory. Nonetheless, improvements seen in the
efficacy of compounds targeting α1H T-type calcium channels indicate significant progress. Ongoing
clinical trials are for the candidates Z944 (Phase II) and ACT-709478 (Phase II) appear promising. These
studies may lead to a new generation of inhibitors with higher selectivity, improved physicochemical
properties, and reduced side effects.

1. Introduction of α1H and α1I in subthalamic nucleus (STN) neurons, while

α1G are prominently expressed in thalamic relay neurons [9,10].
T-type calcium channels are a low-voltage-activated (LVA) cal-
Because T-type calcium channels are linked with the rhyth-
cium channel, named for their characteristic ‘transient (fast
mic firing pattern in key brain regions [11], the regulation of
activation) and tiny (small conductance)’ calcium current regu-
neuronal T-type calcium channels has received increasing
lation of entry into the cell [1]. LVA (T-type) calcium channel
focus as a potential point to of therapeutic intervention to of
genes were first identified by Perez-Reys and colleagues using a
neurodegenerative diseases, such as neuropathic and inflam-
text-based search of the Gene-bank, followed by sequencing
matory pain, epilepsy, and cancer [12–15]. The discovery of
and cloning [2]. T-type channels are composed of a pore-form-
selective blockers for different calcium channel subtypes is
ing α1 subunit (without a β subunit) and α2-δ subunits of
now a significant focus for the development of new drugs
the hetero-multi-transmembrane region of calcium channels
for neuronal calcium channel-related diseases, as each calcium
through the voltage-dependent trans-membrane protein.
channel subtype contributes to the different physiologies of
When classified according to the α1 subunit properties, T-type
neuronal cells. Despite a sustained effort to develop subtype-
calcium channels have three different subtypes: Cav3.1 (α1G),
selective T-type calcium blockers, there are currently no satis-
Cav3.2 (α1H), and Cav3.3 (α1I) [3]. The specific cellular and
factory subtype-selective blockers available clinically for ther-
subcellular distribution of T-type calcium channels has been
apeutic applications.
reported to vary with tissue type, with all three types present
This review covers 43 patents of organic small molecules that
in the brain and peripheral nerve tissues, including dorsal root
have been reported since a 2011 patent review of T-type calcium
ganglia (DRG) and autonomic ganglia, whereas only the α1G
channels blockers (i.e. from 2012–2018) [16]. The molecules taken
and α1H subtypes are present in heart tissue (myocytes and
from the patents have been placed in 8 different categories based
pacemaker cells), smooth muscle tissue, sperm, and endocrine
on their chemical scaffold similarity as follows: (1) fused bicyclic
cells (including thyroid, pancreas, and adrenal) [4–6]. The α1G
pyridine/pyrimidine derivatives; (2) phenylpyrimidinone and phe-
and α1H subtypes are predominantly expressed in skeletal
nyltetrahydropyridine derivatives; (3) triazinone derivatives;
muscle and bone, respectively [7,8]. In the brain, the α1G and
(4) phenylflavone/tetrahydronaphthalene derivatives; (5) carba-
α1H subtypes most prominently expressed in lamina I and α1H
zole/piperidine/piperazine-bearing derivatives; (6) arylsulfona-
are also the most highly expressed in DRG neurons, while α1G
mide derivatives; (7) heteroaromatic amides; and (8) others. Each
and α1I are present at lower levels. Rodents express high levels
general formula presented in the figures has been reorganized

CONTACT Ghilsoo Nam gsnam@kist.re.kr Center for Neuro-Medicine, Brain Science Institute, Korea Institutes of Science and Technology (KIST), Seoul
136-791, Korea; Division of Bio-Medical Science, KIST School, Korea University of Science and Technology Seoul, Seoul, Republic of Korea
© 2018 Informa UK Limited, trading as Taylor & Francis Group
884 G. NAM
Article highlights
● Regulation of neuronal T-type calcium channels is a promising strat-
egy for the treatment of disorders related to neurodegenerative
disease, including neuropathic or inflammatory pain, epilepsy, and
cancer.
● Recent progress in the discovery of selective blockers for different
calcium channels subtypes is very promising for the treatment of
neuronal calcium channel-related diseases due to the widely differing
contributions of each calcium channel subtype to the physiologies of
neuronal cells.
● Numerous scientific efforts to develop subtype-selective T-type cal-
cium channel blockers are underway. Considerable progress appears
to have been made in the efficacy of α1H T-type calcium channel
blockade.
● Clinical trials are currently ongoing for the promising candidates
Z944 (Phase II) and ACT-709478 (Phase II).
This box summarizes key points contained in the article.
and simplified for clarity based on example compounds taken
from the patents.
2. Recent development of t-type calcium channel
blockers
2.1. Fused bicyclic pyridine/pyrimidine derivatives
In 2012, selective α1G T-type calcium channel antagonists
composed of 536 heterocyclic compounds, including ST101
(ZSET1446, IC50 = 0.03 μM), spiro(imidazo(1,2-a)pyridine-3(3H)-
one-3,2′-indane (A, B) (Figure 1), were patented by Zenyaku
Kogyo Kabushiki Kaisha in Japan for the prevention of
Alzheimer’s disease [17]. Kyowa Hakko Kirin Ltd. reported a
series of imidazo(1,2-a)pyrimidine/imidazo(1,2-a)pyridine deri-
vatives (C, D) composed of 183 compounds, which demon-
strated IC50 values under 100 nM against α1H T-type calcium
channels in vitro. They reported several compounds as ther-
apeutic agents for pruritus. Compound 1 was administered
orally (10–30mg/kg) in an in vivo morphine-induced pruritus
disease model, and the inhibitory effect on pruritus evaluated
[18]. Fused and spirocycle compounds, including a spiro
Figure 1. General structure and candidate compound of fused bicyclic derivatives.
[piperidine-,5-cyclopenta[b]pyridine] compound, reported
L-type calcium blocker activity [19].
2.2. Phenylpyrimidinone and phenyltetrahydropyridine
derivatives
Vertex Pharmaceuticals patented novel 4-phenylpyrimidine
compounds as calcium channel inhibitors for the treatment of
pain. In 2013, over 350 4-phenylpyrimidinone compounds were
synthesized, with the general structure E (Figure 2), and evalu-
ated as Na+ and Ca2+ channel blockers for the treatment of pain
[20]. There are no T-type or L-type calcium channel blockers or
sodium channel blockers currently reported. Nifedipine, reported
to be a T-type calcium blocker, is the prototype of dihydropyr-
imidine (DHP) derivatives. Second and third generation DHPs
were developed to improve potency, safety, and pharmacoki-
netic properties [21–23]. SQ32926, developed by Squibb,
demonstrated superior potency, and a longer duration of activity
compared with classical DHPs [24]. In order to improve metabolic
stability, N3-substituted dihydropyrimidine (DHPM) derivatives
were identified to be selective for L-type calcium channels, and
demonstrated inhibitory activity against the α1H T-type subtype.
Five candidate compounds showed promising L-type/T-type
blocking activity and had improved pharmacokinetic properties.
The structure–activity relationship (SAR) studies of DHPMs
demonstrated that the ester moiety is essential for biological
activity. Selectivity against T-type was achieved by replacing of
the alkyl part of the ester with a triazole. Replacing the ester with
amide, hydrazide, or acid functionalities produced loss of L-or
T-type channel inhibitory activities [25]. Further modification of
the hydrazide achieved T-type channel selectivity, with two thio-
semicarbazide derivatives discovered: (2-benzhydryl)thiosemi-
carbazide (3, IC50 Cav3.2 = 0.32 ± 0.10 μM, inhibition of Cav2.2
at 10 μM = 7.64 ± 3.18%), which showed potency against the α1H
subtypes of T-type calcium channels; and (2-benzylidene)semi-
carbazide (2, IC50 Cav3.2 = 3.39 ± 0.10 μM, % inhibition of
Cav2.2 = 31.90 ± 2.39%), the more effective compound. Both
compounds showed an anti-nociceptive effect on formalin and a
Complete Freud’s Adjuvant-induced in vivo model. Compound 3
was the most potent and selective α1H agonist [26].

Figure 2. Phenylpyrimidinone and phenyltetrahydropyridine related derivatives.
1,4-dihydropyridine-3,5-dicarboxylate compounds F are
also dual-acting blockers of L-type/T-type calcium channels
with a remarkable effect on hypertension. 1-diphenylpropyl-
3-methylpyrrolidine derivatives were the most active com-
pounds. The 3S isomer, compound 4, was more potent than
the 3R isomer, compound 5, against both L-type and T-type
calcium channels. The 3R form is the more L-type-selective
compound, as demonstrated by the IC50 values for com-
pound 4 (IC50 L-type/T-type = 0.59/2.28 μM) and compound
5 (IC50 L-type/T-type = 0.93/9.41 μM), respectively [27].
EXPERT OPINION ON THERAPEUTIC PATENTS 885
2.3. Triazinone derivatives
Nissan Chemical Industry Ltd. discovered novel [1.3.5]-triazi-
none compounds G (Figure 3) that showed excellent α1H
T-type calcium channel inhibitory activity, and was useful for
the prevention and/or treatment of pain, chronic disease, and
atrial fibrillation. Compound 6, which has a 4-hydroxy-6-meth-
oxy-3,4-dihydroisoquinoline group, and compound 11, which
has a 7-fluoro-3,4-dihydro-1H-pyrido[3,4-b]indole group of E
functionality, demonstrated the most potency (IC50 values of
49 and 64 nM, respectively). However, the selectivity over
886 G. NAM
Figure 3. [1,3,5]Triazin-2-one derivatives.
other T-type channel subtypes/L-type calcium channels and
the results of in vivo activity against therapeutic targets were
not reported. A 3-trifluoromethylthiophene functionality at the
D position seemed to play an important role for potency, as
the 4-fluorophenyl-substituted compound 9 decreased in
potency 100-fold compared with 3-trifluoromethylthiophenyl-
substituted compounds [28]. Novel 1,3,4-trizin-2-one deriva-
tives (more than 450 compounds) were synthesized and eval-
uated for their T-type calcium channel (α1H) blocking abilities.
In particular, various 4-aryl-substituted 3-piperidine groups
were introduced at the C4 position of the triazinone ring.
Among these synthesized compounds, almost 20 showed
IC50 values below 5 nM. Selected compounds with particularly
strong potency are listed in Figure 3. The most potent blocker,
compound 12 (R)-4-[4-(4-fluorophenyl)-5-hydroxy-5,6-dihydro-
pyridin-1(2H)-yl]-1-{[5-(trifluoromethyl)thiophen-2-yl]methyl}-
1,3,5-triazin-2-(H)-one, showed 0.46 nM efficacy. Compound
13, which has a similar chemical structure except for the C2
methyl group on the triazinone ring, also showed high efficacy
(IC50 = 0.94 nM). These results indicate that the T-type calcium
channel inhibitory activity does not depend significantly on
the C2 methyl substituent. Compound 16, containing a 2-
bromo-thiophene instead of a 2-trifluorothiophene group,
had the same effect [29].
Another series of 1,2,4-triazin-3-one derivatives (H, Figure 4)
with 4-aryl-piperidinyl substituents at the C5 position showed
improved potency over 1.3.5-triazinone derivatives with a fused
ring at the E position. Compound 18, with a 5-hydroxy-4-(5-
methyl)thiophene at the C5 position and a 3-trifluoromethylthio-
phene substituent at the N1 position, was the most potent, as
shown by the IC50 value (10 nM), which is a 10-fold increase in
inhibitory activity against α1H T-type calcium channel compared
with the 1,3,5-triazin-2-none derivative 6. Several other com-
pounds showed excellent inhibitory activity, such as compounds
20 (IC50 = 3.1 nM), 19 (IC50 = 3.4 nM), and 21 (IC50 = 4.8 nM).
Although various heteroaromatic groups have been substituted at
the N1 position, all the compounds with good inhibitory activity
were substituted with a 3-trifluoromethylthiophene group [30].
2.4. Phenylflavone (PFVN)/tetrahydronaphthalene
derivatives
A series of PFVN derivatives were developed to discover
selective and potent T-type calcium blockers by Kinki
 EXPERT OPINION ON THERAPEUTIC PATENTS 887

Figure 3. (Continued).

Figure 4. [1.2.4]Triazin-3-one derivatives.

University and Fuso Pharmaceutical Ltd and patented in and alleviated sodium sulfide–induced hyperalgesia in
2016. The PFVNs, including 6-/8-prenylnaringenin, selec- vivo [31].
tively blocked T-type calcium channels with the IC50 Naoki Toyooka and colleagues designed and synthesized a
around 1 μM compared with L-type calcium channels, novel structure (I, Figure 5) based on the 6-prenylnaringenin
888 G. NAM
Figure 5. 2-Phenylflavone derivatives.
(6-PNG) chemical structure and evaluated T-type channel block-
ing activity. Various substituents, such as OMe, OEt, and Cl, were
introduced at the C6 position on the flavonoid main ring, and the
position and number of substituents were altered. In particular,
the prenyl functionality was converted to either cyclopentyl or
ethyl at the C1 position of the prenyl group and a saturated alkyl
group. Among the synthesized compounds, four with a modified
prenyl group showed improved efficacy over 6-PNG. The in vitro
α1H T-type calcium channel blocking activity of 6-(3-ethylpent-2-
Figure 6. Deuterated tetrahydronapthalene derivatives.
enyl)-5,7-dihydroxy-2-(4-hydroxyphenyl)chroman-4-one com-
pound 22 (IC50 = 260 nM) increased around 4-fold compared
with 6-PNG (IC50 = 801 nM). Introducing a cyclic pattern of
diethylidene on the C6-position substituent of compound 22,
resulted in 6-(2-cyclopentylethyl)-5,7-dihydroxy-2-(4-hydroxy-
phenyl)chroman-4-one (24, IC50 = 460 nM), which also demon-
strated improved activity (although weaker than compound 22).
The introduction of 2-hydroxyphenyl (derivative 23) slightly
decreased activity compared with 4-hydroxyphenyl derivative

22. However, compound 22, the most potent in vitro, showed a
weaker anti-hyperalgesic effect than compound 23 in an in vivo
neuropathic animal model. Compound 23 showed a remarkable
and significant anti-allodynic effect at 10 mg/kg and almost
completely restored partial sciatic nerve ligation (PSNL)-induced
neuropathy at a dose of 20 mg/kg [32].
A novel deuterated tetrahydronaphthalene derivative was
patented by Concert Pharmaceuticals Inc. in the US in 2017 as
a selective T-type calcium channel inhibitor (Figure 6), with
improved absorption, distribution, metabolism, and/or excretion
(ADME) properties [33]. The (1S,2S)-2-(2-((3-(2-benzimidazolyl-
propyl) methylamino)ethyl)-6-fluoro-1,2,3,4-tetrahydro-1-isopro-
pyl-2-naphthyl methoxyacetate dihydrochloride, known as
Mibefradil was deuterated to transfer Compounds 26 and 28.
The NNC 55–0396 with cyclopropyl ester, instead of the methy-
lester found in mibefradil, converted to compounds 27 and 29.
The human microsomal stability of deuterated compounds
improved compared with less deuterated compounds, as
demonstrated by compounds 28 (t1/2 [min] = 7.45) and 29 (t1/2
[min] = 7.15), although only tetradeuterated naphthalene com-
pound 26 (t1/2 [min] = 4.79) and compound 27 (t1/2 [min] = 6.38)
were less stable than mibefradil (t1/2 [min] = 8.52).
4-Isopropylcroman-3-ol derivatives (J, Figure 7), based on the
mibefradil structure and patented as T-type calcium channel
blockers, demonstrated inhibitory activity on Cav3.1 and Cav3.2
channels. Compound 30 had stronger blocking activity for the
only Cav3.2 subtype compared with that of mibefradil [34].
2.5. Carbazole/piperidine/piperazine-bearing derivatives
A series of carbazole derivatives containing piperidine function-
alities were developed by UTI Limited Partnership and
University of Montana as dual T-type calcium blockers/cannabi-
noid agonists [35]. The chemical structure of TTAP-1, which was
developed by researchers at Merck as a selective T-type calcium
blocker (Cav3,3, IC50 = 61 nM) [36], has been reported to inter-
act with cannabinoid receptors; their analogs with substituted
piperidines have also been reported. The carbazole MMP7, a
dual inhibitor of cannabinoids and T-type calcium channels, has
demonstrated efficacy for both neuropathic and inflammatory
Figure 7. 4-Isopropylcroman-3-ol derivatives.
EXPERT OPINION ON THERAPEUTIC PATENTS 889
pain in animal models [37,38]. To optimize α1H T-type channel
selectivity, novel compounds (K) of the combined structure
with TTA-P1 and MMP7 have been synthesized and evaluated
for channel selectivity. Compounds 33 and 34, with piperidine
and piperazine moieties, respectively, were the most selective
for α1H T-type channels (Figure 8). The most potent, compound
33 (α1H % inhibition = 69%, IC50 = 1.48 μM), blocked α1H
channels with around 2-fold higher affinity than α1G (% inhibi-
tion = 44.5%) and α1I (% inhibition = 42.5%). The in vivo acute
pain-alleviation effect of compound 33 was dose-dependent; it
reduced chronic neuropathic pain at a dose of 30 mg/kg in a
partial static nerve injury mouse model. As an indicator of drug-
like properties, physicochemical properties, such as topical
polar surface area (tPSA) and lipophilicity (clogP), were calcu-
lated for compound 33 and showed acceptable values
(tPSA = 66.37 Α2, clogP = 4.59) [39].
N-Piperidinyl acetamide derivatives have been synthesized,
and their use as T-type calcium blockers to treat cardiovascular
disease, epilepsy, cancer, obesity, sleepiness, and pain has been
reported by Taro Pharmaceutical Co. Ltd., Neuromed
Pharmaceutical Ltd., and Zalicus Pharmaceuticals Ltd. Neuromed
Pharmaceuticals patented various substituted N-(piperidin-1-
ylmethyl)benzamide derivatives (L) and evaluated (~620 com-
pounds) them for T-type channel activity including α1G/α1H sub-
types and hERG channels, and tested for in vivo neuropathic pain
alleviation and anti-seizure effect. The most α1G-selective com-
pound, 36, had an N(1-(1-cyclopropanesulfonamido)cyclopentyl)
methyl substituent on the piperidine ring and had an effective
concentration of 2 nM, whereas α1H blocking activity was 400-fold
lower (IC50 = 80 nM). Several compounds – 35, 37, and 39, with an
N-(1,1,1-trifluoro-2-propan-2-yl-amino-2-carboxo-ethyl) substitu-
ent on the piperidine ring, and 38, with an N(1-methylcyclo-
hexyl)-2-propan-amido moiety on the piperidine ring – showed
excellent potency and selectivity against α1H T-channel in vitro
(Figure 9) [40]. In 2018, Taro Pharmaceutical Inc. patented com-
pound Z944 in Europe for use in the treatment of pain, including
peripheral neuropathic, central neuropathic, musculoskeletal,
inflammatory, visceral, and acute pain [41].
Afasci Inc. filed a patent application describing N-substituted
azaspiro[2,5]octane, azaspiro[3.5]nonane, and azaspiro[4.5]decane
890 G. NAM
Figure 8. Carbazole derivatives.
derivatives (with general structure M, Figure 10) as T-type calcium
channel inhibitors for the treatment of neurological (epilepsy,
essential tremor, migraine and Parkinson’s disease) and psychiatric
disorders (anxiety, depression and schizophrenia). Various
N-substituted azaspiro[2,5]octane derivatives showed excellent
α1H T-type channel blocking activity, with IC50 values of
20–200 nM. Compound 41 (Ar = 3-trifluoro-5-fluorophenyl,
R1 = 3,3-dimethylbutane, IC50 = 20 nM) is the most potent inhi-
bitor, whereas compounds 40 (Ar = 3,5-dichlorophenyl) and 42 (3-
trifluoro-5-fluorophenyl) with a t-butyl acetamido group at the N
position of the piperidine ring, have reduced potency (α1H
IC50 = 240 nM and 60nM, respectively). Compound 44, pure
enantiomeric isomers of (R)- or (S)-compound 40, showed 2-fold
improved potency (IC50 = 110 nM). After a comparative evaluation
of the selectivity among the three subtypes of T-type calcium
channels (i.e. other off-target DRG ion channels [Na+, K+], hERG
channels, and cardiac Na+ channels), in vitro, metabolic stability,
and protein binding, selected pharmacokinetic studies were per-
formed for preferred candidate compounds. Candidate com-
pound 44 demonstrated effective relief of neuropathic pain in a
spinal nerve ligation (SNL) rat model. A comparative evaluation
with Z944 and ML218, which have structurally similar scaffolds,
further supported compound 44 as a good candidate. The results
were as follows: blocking activity for T-type calcium channel,
compound 44 (α1H IC50 = 89 nM patch clamp) > Z944
(IC50 = 200 nM) > ML218 (IC50 = 310 nM); pain alleviation in the
SNL model (mechanical % of baseline), compound 44 ≈ ML218
(45 ± 11) > Z944 (25 ± 18); and pain alleviation in the SNL model
(mechanical % of baseline), compound 44 (129 ± 28%) > Z944
(94 ± 38%). The pharmacokinetic parameters of compound 44
were also better than the two reference compounds studied (t1/2
[HLM/RLM] = 36.5/315 min; PPB% Human/rat = 95.7/75.8.3;
plasma stability @ 5 h Human/Rat = 95.7/98.3, AUCtotal/AUCfree
[μL/h] = 4.1/1.0; F [%] = 62; t1/2 plasma [h] iv/po = 3.34/3.66 for
compound 44) [42]. A T-type calcium channel antagonist, imida-
zolyl methyl piperidine, was developed by Merck Sharp & Dohme
Corp. Among 11 derivatives, compound 46 had the strongest
T-type calcium channel inhibition [43].
A novel series of compounds containing N-acetylated cyclic
amine derivatives with the general structure O (Figure 11) were
reported by Zalicus Pharmaceuticals Ltd to be selective calcium
channel modulators. The cyclic amines (4-, 5-, 6-membered cyclic
amines such as azetidines, pyrrolidines, and piperidines) were
substituted at the N position of the ring. The N-substituted cyclic
amine was connected with a linker (such as amide, urea, or
carbamoyl). Over 64 new compounds were synthesized and
investigated for blocking activity of α1G and α1H subtype chan-
nels by a patch-clamp method using HEX cells. The most promis-
ing, compound 59, linked as urea form of N-(1-aminocyclohexyl)-
2-acetyl-piperine with (3,5-bistrifluoromethyl)phenyl and
showed high α1H channel blocking activity in vitro (α1H
IC50 = 30 nM). Compound 47 contained a carbamoyl-type con-
nector and the same substituent (Ar = 3,5-bistrifluorometylphe-
nyl, R = cyclohexylamine), and had decreased blocking activity
compared with compound 48. The trans-2-(1-(2-aminocyclohex-
ylcarbonyl)piperidin-4-yl)-N-(3,5-bis(trifluoromethyl)phenylacea-
mide RR-3/SS-3 was a potent and selective modulator (IC50 α1G/
α1H = 10,000 nM/60 nM). In vivo (rat SNL, 30 mg/kg, PO),

Figure 9. Various substituted amino N-piperidinyl acetamino derivatives.
compound 3 produced anti-allodynia effects of 68 ± 12% (1 h),
76 ± 6% (2 h) and 42 ± 14% (4 h), lower than the effects of the
reference compound gabapentin [44].
A novel series of phenylpyrazolylmethyl-2-(4-substituted
piperidinyl)acetamide derivatives with general structure Q
have been demonstrated as T-type calcium channel blockers
by researchers at the Korea Institute of Science & Technology
(KIST, Figure 12). Twenty-eight compounds were synthesized
and shown to have moderate to high inhibitory activity for
T-type calcium channels. The N-adamantyl-2-(4-(2-((5-isobutyl-
1-phenyl-1H-pyrazole-3-yl)aminomethyl)-2-oxoethyl)piperidin-
1-yl)acetamide compound 49 showed the most potent block-
ing activity with 86.6% and 66.9% inhibition of α1G and α1H,
respectively [45]. Out of over 80 compounds,
N-acetamidopyrazole-substituted piperidine and tetrahydro-
pyridine with representative structure R were synthesized
and evaluated on two subtypes of T-channels (α1G and
α1H). Most compounds in this series had moderate to high
blocking activities (43–78% at 10μM) in both subtypes. The
most promising compound, 4(3-cyanophenyl)piperidine 50,
had high channel blocking activity, 78.06% for α1G and
66.9% for α1H, using the FDSS6000 (Functional Drug
EXPERT OPINION ON THERAPEUTIC PATENTS 891
Screening System, Hamamatsu Photonics) high-throughput
screening (HTS) system [46]. Another research group at KIST
described 1-(isoxazole-5-yl-methylaminoethyl)-4-phenylpiperi-
dine derivatives, which were designed using hypothetical 3D
ligand-based mapping on a pharmacophore model [47], as
potent T-type calcium channel blockers. N-alkylamino-isoxa-
zole-substituted (4-phenyl tetrahydropyridine and piperidine)
derivatives with the general structure S were prepared and
biologically evaluated as T-type calcium channel blockers
with anti-nociceptive effect. Among 116 compounds, the
compound with a 4-(3-trifluoromethyl)phenylpiperidine func-
tionality showed 86.99% inhibition at 10 μM based on
FDSS6000 high-throughput screening. Tetrahydropyridine 51
and piperidine 52 with a 3,4-dichlorophenyl group had the
highest potency for both α1G and α1H T-type calcium chan-
nels with IC50 values of 0.87, 1.37 μM and 1.47, 1.38 μM,
respectively (measured by a patch-clamp assay method).
Compound 51, with a piperidine moiety, had poor pharma-
cokinetic results, except for hERG channel affinity. Compound
52, a tetrahydropyridine, showed a significant alleviation
effect in mechanical allodynia 3 h after oral administration
(100 mg/kg) in a rat SNL model [48,49].
892 G. NAM
Figure 10. Azaspirocyclic and imidazolyl methyl piperidine derivatives.
A series of substituted (2-hydroxy-3-phenoxypropyl)piperi-
dine and piperazine compounds with the general scaffold T
(Figure 13) were synthesized and evaluated as dual inhibitors
of T-type calcium channels and TREK (TWIK-related K+)-1 chan-
nels [50,51]. Over 130 compounds with (2-halophenyloxo- or
thio-)-3-propanol at the N1 position, and various phenyl and
benzyl groups at the N4 position of piperazine were synthesized
and evaluated as T-type calcium blockers. Most compounds
showed low to moderate inhibitory activity (1–62%), which is
lower than the reference compound mibefradil. The relationship
between chirality and biological activity was also investigated.
The compound chirality did not affect the T-type calcium
channel blocking activity, especially in the α1G subtype.
Candidate compound (S)-53 showed selectivity (IC50, α1G/
hERG = 0.76 ± 0.02/13.97 ± 8.3 μM), good bioavailability
(F = 67.25%), and a good AUC ratio (AUCbrain/
AUCplama = 436.8%) [52]. Piperazine derivatives with a 1,5-disub-
stituted pyrazole at the 4N position were prepared, and com-
pound (R)-53–1, 1-(phenyl-5-isopropyl-pyrazolyl-2-aminoacetyl)-
substituted (2-hydroxy-3-phenoxypropyl)piperazine, was
reported to have the highest α1G inhibition (81.07% inhibition
by FDSS 10 mM), although no in vivo data were presented.
Isoxazole/oxazole-conjugated piperazine derivatives with the
general structure U were synthesized and reported to be
T-type calcium channel blockers, especially for the α1G subtype.
Over 70 compounds synthesized and evaluated in vitro showed
inhibitory activity for the α1G subtype using FDSS assay. The
tested compounds demonstrated low to moderate % inhibition

Figure 11. N-acetylated cyclic amine derivatives.
with similar activity between oxazole and isoxazole rings.
Compound 54, 1-(4-(3,4-dimethylphenyl)piperazine-1-yl)-2-((4-
phenyl-5-propyloxazole-2-yl)methylamino)ethenone, had an
IC50 values of 1 μM [53].
Substituted homopiperazine (diazepane) derivatives with
connecting pyrazolylacetamido functionality V (Figure 13) were
prepared by KIST in 2013 to develop potent and selective T-type
calcium channel blockers. Most of the tested compounds
showed moderate to high blocking activity against both two
subtypes (α1G and α1H) and displayed increased activity com-
pared with piperidine derivatives. These compounds also have a
disadvantage in that they have high affinity against hERG chan-
nels (IC50 = 0.2–7.2 μM), except for one compound (55, IC50
hERG = 12.25 ± 0.86 μM) [54].
Recently, G. Nam and colleagues reported that 6-pyrazoly-
lamido-3-N-substituted azabicyclo[3,1,0]hexane derivatives
with the general structure W (Figure 13) were selective
T-type calcium channel blockers. They also demonstrated a
neuropathic pain-alleviation effect in SNL model rats and anti-
cancer activity against various types of cancer cells, including
human fibroblastoma (HT-1080), human glioma (U87-MG),
human prostate carcinoma (LNCaP), human esophageal carci-
noma (KYSE410), human lung carcinoma (A-549), human
breast cancer (MCF-7) and human liver carcinoma (HepG2)
cells. An analog of azabicyclo[3,1,0]hexane, substituted with
benzyl/benzoyl and connected with a (5-isobutyl-1-phenyl)
pyrazole instead of benzimidazole and isoxazole, improved in
EXPERT OPINION ON THERAPEUTIC PATENTS 893
vitro activity and hERG channel selectivity. Particularly, com-
pound 56 exhibited the strongest T-type channel inhibitory
activity (% inhibition α1G/α1H = 80.40/90.27, IC50 = 5.91/
2.89 μM), good metabolic stability, and low CYP 450 inhibitory
activity, but also low oral bioavailability (F = 7.6%).
Nonetheless, this compound displayed a good anti-neuro-
pathic alleviation effect in vivo [55,56].
2.6. Arylsulfonamide derivatives
AbbVie Inc. has described novel benzenesulfonamide-substi-
tuted pyrrolo[1,2a]pyrazines as peripherally acting and selec-
tive T-type calcium blockers with the general structure X
(Figure 14) [57]. Arylpiperazine or benzopyrrolidine function-
ality–containing derivatives displayed high blocking activity
for α1H T-type calcium channel with IC50 values of 0.5–
3.0 μM but showed poor pharmacokinetics. Lead optimization
to improve ADME through modification of sulfonamides led to
the identification of ABT-639 (4-chloro-2-fluoro-N-(2-fluoro-
phenyl)-5-[(8aR)-hexahydropyrrolo[1,2a]pyrazine-2(H)-ylcarbo-
nyl]benzenesulsonamide) in 2013 with reported activity for
diabetic neuropathy as well as being a selective α1H T-type
calcium channel blocker [58]. In the lead compound without a
core substituent benzenesulfonamide group, 2-fluoro, 4-
chloro functionality was introduced to achieve good ADME
properties. This resulted in a plasma clearance rate of 0.55 L/h/
kg, volume distribution of 2.7 L/kg, a half-life of 3.3 h in rats,
894 G. NAM
Figure 12. Various piperidine derivatives.
and bioavailability of 73%. N-methylated sulfonamide deriva-
tives of ABT-639 decreased liver microsomal stability in both
rats and humans (RLM/HLM = 0.04%/<0.01%). The (S)-enantio-
mer of ABT-639 had a lower oral bioavailability (F = 57%) [59];
however, the modified structure without the sulfonamide-sub-
stituted octahydropyrrolo[1,2a]pyrazine displayed L-type cal-
cium channel blocking activity [60].
A series of novel fused benzenesulfonamides bearing substi-
tuted pyrazole derivatives with general structure Y (Figure 14) was
reported to have potent T-type calcium channel inhibitory activity
and a diabetic neuropathic pain-alleviation effect [61,62].
Previously, aryl(1,5-disubstituted-pyrazol-3-yl)methyl sulfona-
mides were reported to be T-type calcium channel blockers and
showed efficacy for neuropathic pain treatment [63]. Candidate
sulfonamide 57 (3-fluorophenyl(1-propyl-5-ispropyl)pyrazol-3-yl)
showed potent activity for T-type calcium channels, but low
microsomal stability (IC50 α1G α1H = 5.65 ± 0.50/5.0 ± 0.61μM,
HLM stability = 13.9%). Fused benzenesulfonamides of a previous
candidate, 2-[{1–(4-fluorophenyl)-5-isobutyl-1H-pyrazole-3-yl}
methyl]-2,3-dihydro[d]isothiazole 1,1,-dioxide showed high block-
ing activity against α1H T-type calcium channels and improved
HLM stability (α1H, IC50 = 2.32 ± 0.73 μM, HLM stability = 101.6%).
In vivo, streptozotocin alleviated diabetic neuropathic pain in rat
models with a rapid onset of mechanical allodynia following oral
administration (100 mg/kg). Furthermore, co-administration with
gabapentin (50mg/kg) at low doses showed a considerable syner-
gistic effect on anti-diabetic neuropathic pain.
Zalicus Pharmaceutical Ltd. described bisalkylsulfone and
dialkylarylsulfone compounds with the general structure Z
(Figure 14) as calcium channel blockers. More than 220 com-
pounds were synthesized and evaluated for L-type (Cav2.2)
and T-type (Cav3.1 and Cav3.2) calcium channel blocking
activity using a fluorescent imaging plate reader screening
system. Most compounds showed high inhibitory activity

Figure 13. Various piperazine derivatives.
against L-type compared with the T-type channel. Among the
tested compounds, 2-chloro-6-methoxy-N-(4-((3-(trifluoro-
methyl)phenyl)sulfonyl)-benzyl)iso-nicotinamide 58 was the
most potent and selective for the T-type channel (IC50,
Cav2.2/Cav3.1/Cav3.2 = 850/2,380/430 nM.). 2-Methyl-2-((3-
(trifluoromethyl)phenyl)-sulfonyl)-N-(3-((3-trifluoromethyl)phe-
nyl)sulfonyl)benzyl)-propanamide 59 had the strongest L-type
channel inhibitory activity (IC50 Cav2.2/Cav3.1/Cav3.2 = 110/
1,410/1,200 nM) [64].
2.7. Heteroaromatic amides
A series of heterocyclic phenyl amide compound synthesized
and described the treatment of neurological and psychiatric
disorders as T-type calcium channel inhibitors by Merck
researchers in 2014 [65, 66]. More than 250 N-disubstituted
benzyl[1,2.3]-triazol-2-yl-arylacetamide derivatives with gen-
eral structure AA were synthesized and measured for the
α1G, α1H, and α1G subtype T-type calcium channels blocking
activity by researchers at Acelion Pharmaceuticals.
EXPERT OPINION ON THERAPEUTIC PATENTS 895
Antagonistic activities of all tested compounds had IC50 values
of 1.7–970 nM for α1H and 1.1–620 nM for α1H. Several potent
compounds with IC50 values <10 nM are presented in
Figure 15.
The most potent compound, compound 60 N-[2-(3,4-
difluoro-benzyl)-2H-[1,2,3]triazol-4-yl]-2(1-methyl-1H-indol-5-
yl)acetamide, had an IC50 value of 6.4 nM, although selec-
tivity and in vivo data were not presented [67]. Idorsia
Pharmaceuticals described a series of pyrazolyl amide deri-
vatives. Over 420 compounds were synthesized and mea-
sured for T-type calcium channel blocking activity. The
tested compounds had IC50 values of 0.3–1210 nM for α1G
and 0.8–1,280 nM for α1I. The blocking activity for α1H
ranged from 3.4 to 9,480 nM. Some examples of potent
α1H blockers are presented in Figure 16. These authors
reported that pyrazolo-3-carboxamides (AB, Figure 16) are
α1G subtype-selective T-type calcium channel blockers and
were drug candidates for the treatment of generalized epi-
lepsy. The optimization of initial candidates improved solu-
bility, brain penetration, and metabolism, and resulted in
896 G. NAM

Figure 14. Arylsulfonamide and fused-benzenesulfonamide derivatives.

Figure 15. Aryl [1,2,3] Triazole acetamide derivatives.

negative Ames test results. Investigating the SAR showed potency. The first candidate displayed triple-potent T-type
that the introduction of an isopropyl or dimethylamino calcium channel blocker activity with no subtype selectivity
group in the para-position of the phenyl ring improved in vitro and excellent in vivo absence epilepsy efficacy in the

Figure 16. Pyrazolyl acetamide derivatives.
WAG/Rij rat model. The SAR studies show that, due to the
metabolism of the amide bond, further optimization was
needed to balance the solubility and stability and to result
in Ames-negative aminopyrazole compounds. Finally, ACT-
709478 (N-(1-((5-cyanopyridin-2-yl)methyl-1H-pyrazol-3-
yl)-2-(4-(1trifluoromethyl)cyclopropyl)phenyl)acetamide) was
discovered as a Phase I clinical candidate, demonstrating
potent blocking activity, good pharmacokinetic properties
(IC50 α1G/α1H/α1I = 6.4/18/7.5 nM; Cbrain = 29 ± 11 nM;
F = 75%; t1/2 = 2.5 h; Cmax = 1,900 nM) and negative Ames
tests. More importantly, this compound was chosen as a
clinical candidate because it did not show species efficacy
differences in rat, dog, and mouse profiling and cynomolgus
T-type calcium channels [68,69].
EXPERT OPINION ON THERAPEUTIC PATENTS 897
2.8. Others
In 2015, aryl-substituted carboxamide derivatives with the
general structures AC and AD (Figure 17) were developed as
T-type calcium or voltage-gated tetrodotoxin-sensitive sodium
channel (Nav1.3, Nav1.7) blockers by RaQualia Pharmaceutical
Inc. A total of 464 compounds were synthesized and evaluated
for channel blocking activity, although no detailed information
about potency was available [70]. Researchers at the University
of Virginia reported that the linear chain form of TH-1177, with
general structure AE, showed anti-proliferative activity of can-
cer cell and T-type calcium channel blocking activity [71].
Fused imidazole derivatives with the general formula AF
(Figure 17) were described as Cav3.2 T-type channel inhibitors
by Toa Eiyo Ltd. Among the 114 synthesized derivatives,
898 G. NAM
Figure 17. Aryl carboxamide derivatives and others.
compounds 71 and 72 presented prominent activities (IC50
values: 1. IC50 = 1.01 μM, 70 IC50 = 1.76 μM) [72].
3. Expert opinion
Introduction of the HTS systems along with the patch-clamp
assay to evaluate the T-type calcium channel inhibitory activity
lead to the variety of small molecule pools of the T-type
calcium channel blockers [73]. Recent studies of T-type cal-
cium channel blockers have focused on two approaches. The
first is to develop subtype-selective T-type channel blockers,
accompanied by other high-voltage calcium channel (L-, N-, P/
Q-, and R-type) selectivity. The second is to discover dual or
multi-channel blockers, such as T-/N-type, Na+-/T-type, and T-/
TWIK-type channels. This indicates that T-type calcium channel
blockers could apply into various CNS-related diseases, such as
neuropathic pain, epilepsy, Parkinson’s disease, sleep disorder,
essential tremor and absence seizure [74–76]. Advances in
pharmacological research have shown that each subtype
T-type calcium channels are involved in sensory transmission
and pain perception, leading to the development of subtype-
selective T-type calcium blockers as a treatment for neuro-
pathic pain. Particular focus has been paid to α1H T-type
calcium channel blockers in order to find new candidates.
Several compounds have excellent α1H T-type calcium
channel blocking activity with IC50 values in the milli-to-nano-
molar range and good drug-like properties; however, subtype
selectivity is still lacking. It has been reported that TTAP-1,
developed by Merck Co., can act as a potent α1I subtype
blocker. In this review, the triazinone derivatives displayed
exclusively potent α1H T-type calcium channel blocker activity,
and carbazole compounds were potent α1G subtype channel
blockers. Aryl triazole/imidazole amide derivatives showed
excellent triple-subtype T-type calcium channel blocking activ-
ity, although the subtype selectivity was still unsatisfactory.
This review described diverse chemical scaffolds (with their
general formulas) and the efficacy of each subtype of the most
promising compounds. It is difficult to classify them into cate-
gories based on the T-channel activity and structural charac-
teristics at present. Improvement of the efficacy of α1H T-type
calcium channel, the physicochemical properties, and DMPK
profiles seemed to make progress considerably.
Several studies by Medium-sized Pharma, academic organiza-
tions, and Big Pharma are currently underway to develop subtype-
selective T-type calcium channel blockers. It was recently reported
that an antiparkinsonian effect was lacking in MPTP-treated par-
kinsonian monkeys following injections with the pan-T-type cal-
cium blocker ML218 (CID45115620), a clinical candidate to treat
Parkinson’s disease [77]. Ethosuximide failed to treat neuropathic
pain in humans [78]. Both compounds failed due to adverse and
sedative effects observed in dosing studies. ABT-636 and MK-8998
also failed in human clinical trials for pain/schizophrenia treatment
[79,80]. Therefore, subtype-selective T-type calcium channel block-
ers have attracted attention due to their potential to offer a new

generation of safe and effective drugs for pain-related diseases,
including neuropathic, diabetic, and cancer-related pain.
Mismatched efficacy in vivo, based on in vitro predictions designed
to overcome disadvantages associated with the evaluation of
neuropathic pain and epilepsy, is a complicating factor in in vivo
models. Nevertheless, most compounds tested in an in vivo animal
model have demonstrated effectiveness in managing pain (inflam-
matory, acute, and neuropathic) and in some cases demonstrated
fast-acting neuropathic pain alleviation compared with a reference
compound, such as gabapentin. Therefore, combination therapy
or a systemic dose control treatment with the primarily used pain-
treatment drug may play an important role in alleviating neuro-
pathic, diabetic, and late-stage cancer pain.
The expansion of research into T-type calcium channel
antagonists may be required to treat conditions such as hear-
ing loss, as several recent studies have shown that T-type
calcium channels contribute to calcium availability during
acquired sensory neuronal hearing loss [81,82]. Three subtypes
of T-type calcium channel are expressed at different levels in
the cochlea of 6–8-week-old C57BL/6J mice [83]. Treating this
type of hearing loss is typically difficult in a clinical setting and
there are currently no approved therapies available.
Clinical trials are currently ongoing for the promising candi-
dates Z944 (Phase II) and ACT-709,478 (Phase II). The results of
these studies may lead to a new generation of T-type calcium
channel blockers, improving physicochemical properties and
selectivity, while minimizing possible side effects. The develop-
ment of novel effective and subtype-selective T-type calcium
channel blockers for the treatment of CNS-related diseases,
including neuropathic pain and epilepsy, should be achievable
with the joint efforts of biological, medicinal, pharmacological,
and clinical researchers and suitable funding.
Funding
This work is supported by the Original Technology Research Program
(NRF-2016M3C7A1904344) and Brain research program ICT & Future
Planning (NRF-2016M3C7A1913845) funded by the National Research
Foundation of Korea (NRF). This work was also supported by Korea
Institute of Science and Technology (Grant: 2E27870).
Declaration of interest
GN declares that they work for the Division of Bio-Medical Science, Korea
Institutes of Science and Technology.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other
relationships to disclose.
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EXPERT OPINION ON THERAPEUTIC PATENTS 901
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