Content uploaded by Maurizio Romano
Author content
All content in this area was uploaded by Maurizio Romano
Content may be subject to copyright.
C12H14N4O
Mol wt: 230.2658
EN: 649113
SUMMARY
The identification of new targets for specific and effective therapies poses
new challenges for the treatment of several muscle diseases causing
weakness (e.g., amyotrophic lateral sclerosis [ALS]). Recent advances
have pointed out that sarcomeres may represent potentially useful phar-
macological targets. As a result, screening studies for activators of the
troponin–tropomyosin complex have resulted in the identification and
optimization of a selective fast skeletal troponin activator, tirasemtiv
(CK-2017357), which sensitizes fast muscle fibers to calcium. The action
of this drug causes an increase in muscle force development at submax-
imal activation. In vitro and in vivo experiments have further supported
the proposed mechanism of action of tirasemtiv. Encouragingly, phase
I and phase II trials in ALS patients have shown a favorable safety pro-
file and efficacy in functional improvements of skeletal muscle perform-
ance and in reducing fatigability. For this reason, the target enhance-
ment of contractility derived from administration of tirasemtiv may be
capitalized upon for the treatment of several variable pathologies, from
cardiac and skeletal muscle pathologies to other neuromuscular disor-
ders and claudication.
Key words: Amyotrophic lateral sclerosis – Skeletal muscle perform-
ance – Tirasemtiv – CK-2017357
SYNTHESIS*
Condensation of 2-amino-3,5-dibromopyrazine (I) with neat 3-amino -
pentane (II) under microwave irradiation at 150 °C yields the di-
aminopyrazine (III), which is then subjected to cyclization with CDI in
refluxing THF to give 6-bromo-1-(3-pentyl)imidazo[4,5-b]pyrazin-2-ol
(IV). Sonogashira cross-coupling of aryl bromide (IV) with (trimethylsil -
yl)acetylene (V) in the presence of PdCl2(PPh3)2, CuI and Et3N in DMF
at 80 °C affords adduct (VI), which is finally desilylated by treatment
with KF in MeOH/THF/H2O (1). Scheme 1.
BACKGROUND
Striated muscles are responsible for the voluntary movement of dif-
ferent body parts. The contractile structures of striated (or skeletal)
muscles contain repetitive arrays of actin and myosin. The precise or-
ganization of these filaments allows the coordinated action of the
contractile system in order to generate force and finely tuned direc-
tional activity (2-6).
Myopathies are either inherited, the most common being muscular
dystrophies, congenital, mitochondrial and metabolic myopathies, or
acquired as a result of several different pathological processes, such
as inflammatory, infectious, toxic-induced disorders, and from other
systemic conditions (7, 8). Acquired myopathies can also be the con-
sequence of prolonged immobilization, chronic bed rest or physical in-
activity (9-11). Importantly, some of the disease mechanisms leading
to significant loss of muscle mass/strength can also be involved in
the worsening of skeletal muscle functions induced by microgravity
(12) and aging (13, 14), as well as in the pathogenesis of neoplastic
cachexia (15).
157
THOMSON REUTERS
Drugs of the Future 2013, 38(3): 157-162
Copyright © 2013 Prous Science, S.A.U. or its licensors. All rights reserved.
CCC: 0377-8282/2013
DOI: 10.1358/dof.2013.38.3.1915460
CH N
NN
OH
N
CH3CH3
M. Romano1and E. Buratti2. 1Department of Life Sciences, University of Trieste, Via
A. Valerio 28, 34127-Trieste, Italy; 2International Centre for Genetic Engineering and
Biotechnology, Padriciano 99, 34149-Trieste, Italy. E-mail: mromano@units.it.
*Synthesis prepared by J. Bolòs, R. Castañer. Thomson Reuters, Provença 398, 08025
Barcelona, Spain.
MONOGRAPH
TIRASEMTIV Troponin Activator
Rec INN; USAN Treatment of Amyotrophic Lateral Sclerosis
CK-2017357
1-(1-Ethylpropyl)-6-ethynyl-1H-imidazo[4,5-b]pyrazin-2-ol
InChI: 1S/C12H14N4O/c1-4-8-7-13-10-11(14-8)16(12(17)15-10)9(5-2)6-3/h1,7,9H,5-6H2,2-3H3,(H,13,15,17)
In many cases, these conditions are not fatal, and typical symptoms
consist of atrophy that causes general muscle weakness and move-
ment problems. However, some myopathies can be degenerative and
become more severe over time, leading to disability and increased
mortality (8, 16-19).
To date, several attempts at slowing down the progression of degen-
erative myopathies have been made. In particular, studies on nutri-
tional and respiratory support, as well as exercise, have improved the
management of symptoms in some cases (20-28). However, these
improvements are limited, and as a consequence, there is a high level
of interest in identifying other therapeutic options for the treatment of
these degenerative myopathies.
In recent years, basic and translational studies have shed light on the
mechanisms involved in the pathophysiology of the contractile ma-
chinery (29). The insights gained have been useful in identifying novel
targets for improved therapeutic intervention (30). As a common fea-
ture of many different myopathies consists in the loss of motor neu-
rons, which causes progressive muscle malfunction and weakness,
researchers have started considering the development of therapeutic
strategies that might bypass deficits in motor neuron stimulation by
counteracting muscular weakness and fatigue.
The sarcomere represents the hub of skeletal muscle contraction, and
consequently, modulation of its activity currently represents one of
the possible and most promising targets identified so far (31-33). The
structure of sarcomere is highly organized and its function depends on
the binding of myosin to actin: this interaction is regulated by the
actin-associated proteins, tropomyosin and troponin, depending on
the intracellular levels of calcium ions (34). In fact, the release of Ca2+
from the sarcoplasmic reticulum and its binding to the troponin com-
plex plays a pivotal role in skeletal muscle contraction. For this rea-
son, it has been hypothesized that regulating the sensitivity of the
troponin–tropomyosin complex to calcium levels may help to artifi-
cially improve the force of muscle contraction and might represent
an appealing alternative approach for the treatment of neuromuscu-
lar disorders.
To date, a drug capable of modulating sarcomere activity is repre-
sented by omecamtiv mecarbil (CK-1827452), a myosin activator that
acts independently of calcium and has been tested for the treatment
of heart failure (35, 36). Recently, CK-1909178, a fast skeletal troponin
activator, was identified as a compound capable of sensitizing the sar-
comere to calcium and increasing skeletal muscle force in vitro and in
situ (37, 38). This compound is currently being tested for the treat-
ment of congenital myopathies associated with tropomyosin muta-
tions (39).
On the other hand, with respect to affecting skeletal muscle reactiv-
ity and strength, a second compound, tirasemtiv (CK-2017357), has
recently made its appearance. The activity of this compound appears
to specifically increase the sensitivity of fast skeletal muscle to cal-
cium, an effect that is achieved by decreasing the amount of calcium
required to produce a comparable force in fast muscle fibers (40). In
this way, direct modulation of fast skeletal muscle contractility might
represent an innovative therapeutic option for improving physical ac-
tivity in diseases in which neuromuscular function is compromised.
Importantly, this compound may be particularly useful for patients
affected by amyotrophic lateral sclerosis (ALS), where respiratory dis-
tress and failure are the consequence of a progressive weakening of
158
TIRASEMTIV M. Romano and E. Buratti
THOMSON REUTERS – Drugs of the Future 2013, 38(3)
CH N
NN
OH
N
CH3CH3
N
NN
OH
N
CH3CH3
TMS
Br N
NN
OH
N
CH3CH3
CH
TMS
NH
CH3CH3
N
NNH2
Br
Br
N
NNH2
Br
NH2
CH3CH3
KF
CDI
(I)
(II)
(III)
(IV)
(V)
(VI)
PdCl2(PPh3)2, CuI
Et3N
Scheme 1. Synthesis of Tirasemtiv
the diaphragm and intercostal muscles. In patients affected by this
disease, it has been proposed that tirasemtiv might be helpful for in-
creasing the strength of the different skeletal muscles, and in partic-
ular, those crucial for breathing.
In this article we review the preclinical and clinical data on tirasemtiv
and its applications for the potential treatment of the muscular weak-
ness associated with ALS.
PRECLINICAL PHARMACOLOGY
In vitro experiments have evaluated the effects of tirasemtiv on iso-
metric skinned fibers from rabbit psoas (fast) and rat soleus (slow)
cardiac muscles. In these experiments, single skinned fibers were in-
cubated with different concentrations of buffered calcium and
tirasemtiv to obtain isometric length-tension curves through a force
transducer. Similar experiments were then repeated on permeabi-
lized human fast skeletal muscle fibers. In all these cases, tirasemtiv
treatment was found to increase submaximal force development in
both rabbit and human fast skeletal muscles. However, the activity of
tirasemtiv on slow skeletal myofibrils was 10-fold lower than that ob-
served for fast fibers. Importantly, the specificity of fast skeletal my-
ofibrils was also supported by the observation that the effects of this
compound on cardiac muscles were negligible (40). In keeping with
these conclusions, tirasemtiv showed specific activity only for fast
skeletal myofibrils both when tested on bovine masseter (slow) and
bovine cardiac muscle (fast), where it induced a significant leftward
shift of myosin ATPase activity (pCa50 = 5.61 vs. 6.52, i.e., controls vs.
treated). By measuring the variations of the myosin ATPase rate in re-
sponse to ascending doses of tirasemtiv at a fixed calcium concen-
tration, the EC50 for tirasemtiv was 390 ± 17 nM (41).
As a follow-up study, two in vivo running models were set up in healthy
rats to assess the effects of tirasemtiv on resistance to fatigue. In the
first model, based on an aerobic fatigue assay (treadmill running time),
treatment with tirasemtiv at doses of 10 and 20 mg/kg (vs. controls)
produced a significant improvement of 50% in running time in rats. In
the second model, based on an anaerobic fatigue assay (rotarod run-
ning time), a significant improvement of 100% in running time was ob-
served in rats treated with tirasemtiv at doses of 1 and 3 mg/kg vs. the
administration of potential control anti-fatigue treatments (42). These
in vivo results were also substantially confirmed in a rodent model of
myasthenia gravis caused by treatment with an inhibitory nicotinic
acetylcholine receptor antibody that induced muscle weakness and fa-
tigue (41, 43). In this model, an increase in muscle force in situ and in
fatigue endurance after prolonged stimulation were observed soon
after administration of tirasemtiv. Moreover, tirasemtiv treatment in-
creased grip strength by more than 50% over baseline (41).
PHARMACOKINETICS AND METABOLISM
The pharmacokinetic properties of tirasemtiv were evaluated in mice,
rats, dogs, rabbits and monkeys after: a) single-dose oral and/or in-
travenous administration; or b) repeated doses following oral admin-
istration. In both cases, the results indicated that the systemic
clearance of the drug was low and that the distribution volume was
from low to moderate in all the species examined, with monophasic
elimination kinetics. Following oral administration, mice, rats and
dogs showed a high bioavailability, while gender differences were ob-
served only in rats (values higher in females than in males) (44).
The pharmacokinetics of single and multiple oral doses of tirasemtiv
were examined in two phase I clinical trials involving healthy subjects
(44, 45). Two formulations (API in capsule and a liquid suspension)
were used for oral single-ascending-dose studies (ranging from 20
to 2500 mg/day under fasting conditions). In healthy subjects, after
administration of a single oral ascending dose, the systemic exposure
of tirasemtiv was high, with monophasic elimination kinetics (median
terminal t1⁄2 = 11.3 hours) and apparent clearance and volume of dis-
tribution relatively dose-independent. In the tested dose range, the
AUCinf was found to be dose-proportional and independent of the for-
mulation. On the other hand, the opposite was observed for Cmax. The
API in capsule formulation was used to perform a multiple-dose study
at two dose levels: 250 and 375 mg/day for 7 days. After multiple oral
daily dosing, the steady-state concentrations were achieved by day 7
and drug accumulation was found to be minimal (i.e., < twofold) (46).
Finally, single oral doses of either 250 or 500 mg/day were adminis-
tered for 7 months in patients suffering from ALS. The plasma concen-
trations of the compound proved to be similar to those observed in
healthy volunteers, with a Cmax reached between 4 and 6 hours and
drug levels still dosable after 24 hours.
In conclusion, tirasemtiv has demonstrated desirable pharmacoki-
netic properties in healthy subjects following single and multiple oral
doses. These pharmacokinetic results support the continued clinical
development of this novel agent for the potential treatment of chronic
neuromuscular diseases such as ALS (as a once-daily oral therapy).
SAFETY
In general, tirasemtiv proved to be well tolerated and no serious ad-
verse events (AEs) were reported either after single or multiple doses
(45, 47). The most common AEs were dizziness, generalized fatigue,
headache, euphoria and muscle spasms. All these events were gen-
erally mild in severity. Dizziness was reported by 21% of patients re-
ceiving 250 mg/day of tirasemtiv as single oral doses and by 49% of
those receiving 500 mg/day. This was the most frequent and dose-re-
lated side effect compared to placebo. In all but one of the patients,
the dizziness ceased after the second day of drug administration (46).
When tested in a clinical trial evaluating the efficacy of a single dose
of tirasemtiv on peripheral artery disease and symptomatic claudica-
tion, serious drug-related AEs were reported in two patients after dos-
ing tirasemtiv at 750 mg/day. Although hospitalized, they fully
recovered without the need for any specific therapy. Cholecystitis fol-
lowing the second dose of this study (i.e., 500 mg/day) was reported
in a third patient. However, this AE was considered to be unrelated to
administration of the study drug.
CLINICAL STUDIES
To date, several clinical trials have been performed using tirasemtiv.
In the first trial, phase I was divided in two parts. In the first part of the
study (part A), the safety, tolerability and pharmacokinetics were eval-
uated following administration of increasing single oral doses in
healthy volunteers. No intolerable AEs were observed after adminis-
tering up to 2000 mg/day of the drug as single oral doses. On the
other hand, the second part of the study (part B) aimed at evaluating
the pharmacodynamic effects of tirasemtiv on skeletal muscle (tib-
ialis anterior) function. This was performed after single oral doses of
159
M. Romano and E. Buratti TIRASEMTIV
THOMSON REUTERS – Drugs of the Future 2013, 38(3)
250, 500 and 1000 mg/day and during a four-period crossover de-
sign. A statistically significant increase in muscle force was observed
after drug administration compared to the placebo treatment. Over-
all, these results confirmed the observations made during the pre-
clinical studies (see above).
Concomitantly to part B (single-dose trial), a second phase I trial was
designed to evaluate the safety, tolerability and pharmacokinetic pro-
file of multiple oral doses of tirasemtiv in healthy male volunteers.
During this trial, high drug systemic exposure and low intersubject
variability were generally reported.
Following these phase I trials, four phase II trials in ALS have been
completed so far.
The first study was aimed at demonstrating tirasemtiv pharmacody-
namic effects on skeletal muscle function and fatigability in patients
with ALS (ClinicalTrials.gov Identifier: NCT01089010). This double-
blind, randomized, placebo-controlled, three-way crossover study en-
rolled 67 ALS patients randomized to 1 of 6 different treatment
protocols. Three dosing periods characterized each treatment se-
quence, during which patients received a single oral dose of placebo
(250 or 500 mg of tirasemtiv). A washout period of 6-10 days spaced
out the doses for each patient. Following tirasemtiv administration,
significant improvements were observed in functional parameters re-
lated to maximal voluntary muscle strength, especially regarding the
development of fatigue at maximal and submaximal voluntary mus-
cle contraction levels.
The second trial analyzed the safety and tolerability after multiple
daily doses of tirasemtiv in 50 patients with ALS randomized to 1 of 4
different treatment groups, and receiving daily oral doses of placebo
and 125, 250 or 375 mg of the drug for 14 days (ClinicalTrials.gov Iden-
tifier: NCT01378676). This study was divided in two parts. In the first
part of the study, 24 ALS patients were enrolled to assess the tolera-
bility and pharmacokinetics of tirasemtiv administered orally at doses
of 125, 250 and 375 mg/day for 2 weeks, without coadministration
of riluzole. In the second part of the trial, the patients received the
same tirasemtiv dosing (or placebo) with oral coadministration of 50
mg/day of riluzole for 14 days. No significant differences in the re-
sponse to the treatment were found, possibly because of the limited
number of the enrolled patients examined and the large interpatient
variability. However, a positive correlation between the increase in
daily oral doses of tirasemtiv and the response to treatment was de-
tected. In particular, four patients reported improvements in the
global assessments and three patients reported improvements in the
ALS Functional Rating Scale-Revised (ALSFRS-R) after administra-
tion of 375 mg/day of tirasemtiv. Improvements in the Maximal Vol-
untary Ventilation (MVV) levels were reported in patients after 2 weeks
of oral dosing at 375 mg/day, in comparison to those observed at 24
hours after a single oral dose of 500 mg/day of tirasemtiv in part A
(45). In the second part of this trial, tirasemtiv appeared to be well
tolerated both when administered alone and concomitantly with rilu-
zole (46, 48). Apparently, tirasemtiv did not cause significant changes
in blood or ECG parameters, and when coadministered with riluzole
it caused a dose-dependent increase in the plasma levels of riluzole
without changing the profile of AEs (46).
The third study (ClinicalTrials.gov Identifier: NCT01486849) tested
the safety, tolerability, pharmacokinetics and pharmacodynamic ef-
fects of escalating multiple doses of tirasemtiv to an individual pa-
tient maximum tolerated dose, using a within-patient twice-daily
dose-titration regimen in 28 ALS patients taking 50 mg riluzole once
daily. Randomized patients were required to decrease their riluzole
daily dose to 50 mg for 7 days. After a 1-week period patients started
to receive placebo or the titration of active tirasemtiv (while continu-
ing to take riluzole at 50 mg/day). Initially, patients received an oral
dose of tirasemtiv of 250 mg/day (125 mg twice daily) or matching
placebo for 7 days. In the following 7 days, the tirasemtiv daily dose
was escalated to 375 mg (125 mg in the morning and 250 mg in the
evening) or matching placebo tablets b.i.d. for 7 days. Finally, for an-
other 7 days, patients received a total daily dose of 500 mg (250 mg
twice daily) or matching placebo. A final dose of 250 mg of tirasem-
tiv or placebo was administered in the morning on day 22. The main
findings of this clinical trial were the functionally positive responses to
oral tirasemtiv administration, with a generally safe and well-toler-
ated drug titration seen to occur at 250 mg twice daily.
Finally, a fourth phase II study of tirasemtiv (ClinicalTrials.gov Identi-
fier: NCT01131013) was also carried out in patients with peripheral ar-
tery disease and symptomatic claudication (49). This was a
double-blind, randomized, placebo-controlled, three-way crossover
study that examined the pharmacokinetics and pharmacodynamics of
tirasemtiv. For this study, a bilateral heel raise test was set up ad hoc
in order to evaluate the calf muscle performance in these patients.
Initially, the effects of single oral doses of tirasemtiv were tested in
patients with peripheral artery disease and claudication. In these pa-
tients, the possible changes in skeletal muscle function, as well as
fatigability, were evaluated. In parallel, the possible correlation be-
tween tirasemtiv administration and its plasma concentrations was
assessed. Finally, the pharmacodynamic effects, safety and tolerabil-
ity of single oral doses of tirasemtiv were examined. For this study, 61
patients were enrolled in a 3-period crossover trial with a washout pe-
riod of 6 to 10 days between each of the 3 treatments. In particular, 56
patients were treated with single oral doses of tirasemtiv of 375
mg/day, 33 patients with 750 mg/day and 57 patients with single
doses of placebo. Following a protocol amendment during the course
of the study, 33 patients were dosed as initially indicated, while the re-
maining 27 received 500 mg/day of tirasemtiv. The peak plasma con-
centrations of the compound were reached between 3 and 6 hours
after dosing. The performance of skeletal muscle function and fati-
gability were subsequently monitored before each dose, and then
again after 3 and 6 hours. Furthermore, the distance walked by the
patient during a 6-minute period was measured 4 hours after dos-
ing. These tests showed that tirasemtiv promoted a general improve-
ment in calf muscle functions, and that its effects were dose-
dependent (with the best performance observed with doses of 750
mg/day after 6 hours). At 6 hours after dosing, a statistically signifi-
cant median increase from work baseline of 5.7 kg/m2was observed.
These performance increases were correlated with tirasemtiv dosing
and its plasma levels at the time of the test. On the other hand, a de-
crease was observed in the walking test related with dosing and
plasma levels of tirasemtiv. Indicatively, the mean baseline 6-minute
walk distance measured was 1,079 feet.
Further studies will be required to explore whether changes in the
posology of tirasemtiv might abate the dose-related AEs observed.
160
TIRASEMTIV M. Romano and E. Buratti
THOMSON REUTERS – Drugs of the Future 2013, 38(3)
CONCLUSIONS
Tirasemtiv is a fast skeletal muscle troponin activator. This compound
was developed for the potential treatment of conditions and diseases
associated with debilitating muscular diseases, muscle weakness, as
well as the effects of natural aging. Overall, tirasemtiv has shown a
real ability to increase skeletal muscle strength in response to motor
neuron signals, as well as to decrease the rate of muscle fatigue. In
this context, concomitantly with neuronal degeneration and reduc-
tion in motor neuron signaling, the muscles of ALS patients lose
strength and endurance. Therefore, tirasemtiv can hopefully counter-
act these effects at the muscle level and help preserve their normal
function longer. Currently tested in different phase II clinical trials,
tirasemtiv has recently been granted orphan drug status both in the
U.S. by the Food and Drug Administration (FDA) and in Europe by the
European Medicines Agency (EMA) for the potential treatment of ALS.
Although larger trials will be needed to strengthen any conclusions,
the promising results obtained so far in ALS patients further support
the characterization of its potential effects in the treatment of other
disorders/conditions associated with muscle debilitation, such as sar-
copenia, cachexia, myasthenia gravis, as well as aging (28).
SOURCE
Cytokinetics, Inc. (US).
ACKNOWLEDGMENTS
This work was supported by the University of Trieste - Finanziamento
per Ricercatori di Ateneo and AriSLA (TARMA).
DISCLOSURES
The authors state no conflicts of interest.
REFERENCES
1. Muci, A., Finer, J.T., Lu, P.-P., Russell, A.J., Morgan, B.P., Morgans, D.J. Jr.
(Cytokinetics, Inc.). Certain chemical entities, compositions and methods.
EP 2069352, JP 2009545596, US 2008146561, US 7598248, US
8227603, US 8299248, WO 200801669.
2. Lange, S., Ehler, E., Gautel, M. From A to Z and back? Multicompartment
proteins in the sarcomere. Trends Cell Biol 2006, 16(1): 11-8.
3. Kontrogianni-Konstantopoulos, A., Ackermann, M.A., Bowman, A.L.,
Yap, S.V., Bloch, R.J. Muscle giants: Molecular scaffolds in sarcomerogen-
esis. Physiol Rev 2009, 89(4): 1217-67.
4. Tskhovrebova, L., Trinick, J. Roles of titin in the structure and elasticity of
the sarcomere. J Biomed Biotechnol 2010, 2010: 612482.
5. Crawford, G.L., Horowits, R. Scaffolds and chaperones in myofibril assem-
bly: Putting the striations in striated muscle. Biophys Rev 2011, 3(1): 25-32.
6. Gokhin, D.S., Fowler, V.M. The sarcoplasmic reticulum: Actin and tropo-
modulin hit the links. Bioarchitecture 2011, 1(4): 175-9.
7. Myopathies (http://www.ncbi.nlm.nih.gov/books/NBK1116/). In:
GeneReviews. R.A. Pagon et al. (Eds.). Seattle, Washington, 1993-2013.
8. Fredericks, C.M. Disorders of muscles: The myopathies In:Pathophysiolo-
gy of the Motor Systems: Principles and Clinical Presentations. L.K. Sal-
adin, C.M. Fredericks (Eds.). F.A. Davis Company: Philadelphia, 1996,
293-401.
9. Gabriel, D.A., Kamen, G., Frost, G. Neural adaptations to resistive exercise:
Mechanisms and recommendations for training practices. Sports Med
2006, 36(2): 133-49.
10. Suetta, C., Magnusson, S.P., Beyer, N., Kjaer, M. Effect of strength training
on muscle function in elderly hospitalized patients. Scand J Med Sci Sports
2007, 17(5): 464-72.
11. Clark, B.C. In vivo alterations in skeletal muscle form and function after dis-
use atrophy. Med Sci Sports Exerc 2009, 41(10): 1869-75.
12. Ferrando, A.A., Paddon-Jones, D., Wolfe, R.R. Alterations in protein meta -
bo lism during space flight and inactivity. Nutrition 2002, 18(10): 837-41.
13. Trappe, T. Influence of aging and long-term unloading on the structure and
function of human skeletal muscle.Appl Physiol Nutr Metab 2009, 34(3):
459-64.
14. Vernikos, J., Schneider, V.S. Space, gravity and the physiology of aging:
Parallel or convergent disciplines? A mini-review. Gerontology 2010, 56(2):
157-66.
15. Tisdale, M.J. Mechanisms of cancer cachexia. Physiol Rev 2009, 89(2):
381-410.
16. Ishikawa, K. Cardiac involvement in progressive muscular dystrophy of the
Duchenne type. Jap Heart J 1997, 38(2): 163-80.
17. Engel, W.K., Askanas, V. Inclusion-body myositis: Clinical, diagnostic, and
pathologic aspects. Neurology 2006, 66(2, Suppl. 1): S20-9.
18. Gros-Louis, F., Gaspar, C., Rouleau, G.A. Genetics of familial and sporadic
amyotrophic lateral sclerosis. Biochim Biophys Acta 2006, 1762(11-12):
956-72.
19. Udd, B. Distal muscular dystrophies. Handbook of Clinical Neurology. P.J.
Vinken and G.W. Bruyn (Eds.). 2011, 101: 239-62.
20. Cherin, P. Treatment of inclusion body myositis. Curr Opin Rheumatol
1999, 11(6): 456-61.
21. McDonald, C.M. Physical activity, health impairments, and disability in
neuro muscular disease. Am J Phys Med Rehab 2002, 81(11, Suppl.):
S108-20.
22. Paddon-Jones, D. Interplay of stress and physical inactivity on muscle loss:
Nutritional countermeasures. J Nutr 2006, 136(8): 2123-6.
23. Bailey, P.P., Miller, R.R. 3rd, Clemmer, T.P. Culture of early mobility in
mechanically ventilated patients. Crit Care Med 2009, 37(10, Suppl.):
S429-35.
24. Glover, E.I., Phillips, S.M. Resistance exercise and appropriate nutrition to
counteract muscle wasting and promote muscle hypertrophy. Curr Opin
Clin Nutr Metab Care 2010, 13(6): 630-4.
25. Peterson, M.D., Gordon, P.M. Resistance exercise for the aging adult: Clin-
ical implications and prescription guidelines. Am J Med 2011, 124(3): 194-8.
26. Downing, J., Balady, G.J. The role of exercise training in heart failure. J Am
Coll Cardiol 2011, 58(6): 561-9.
27. Ashworth, N.L., Satkunam, L.E., Deforge, D. Treatment for spasticity in
amyotrophic lateral sclerosis/motor neuron disease. Cochrane Database
Syst Rev 2012, 2: CD004156.
28. von Haehling, S., Stepney, R., Anker, S.D. Advances in understanding and
treating cardiac cachexia: Highlights from the 5th Cachexia Conference.Int
J Cardiol 2010, 144(3): 347-9.
29. Nowak, K.J., Ravenscroft, G., Laing, N.G. Skeletal muscle alpha-actin dis-
eases (actinopathies): Pathology and mechanisms. Acta Neuropathol
2013, 125(1): 19-32.
30. Kho, A.L., Perera, S., Alexandrovich, A., Gautel, M. The sarcomeric
cytoskeleton as a target for pharmacological intervention. Curr Opin Phar-
macol 2012, 12(3): 347-54.
161
M. Romano and E. Buratti TIRASEMTIV
THOMSON REUTERS – Drugs of the Future 2013, 38(3)
31. Gordon, A.M., Ridgway, E.B., Yates, L.D., Allen, T. Muscle cross-bridge
attachment: Effects on calcium binding and calcium activation. Adv Exp
Med Biol 1988, 226: 89-99.
32. Arteaga, G.M., Warren, C.M., Milutinovic, S., Martin, A.F., Solaro, R.J.
Specific enhancement of sarcomeric response to Ca2+ protects murine
myocardium against ischemia-reperfusion dysfunction. Am J Physiol
Heart Circ Physiol 2005, 289(5): H2183-92.
33. Tunnemann, G., Karczewski, P., Haase, H., Cardoso, M.C., Morano, I. Mod-
ulation of muscle contraction by a cell-permeable peptide. J Mol Med
2007, 85(12): 1405-12.
34. Gomes, A.V., Potter, J.D., Szczesna-Cordary, D. The role of troponins in
muscle contraction. IUBMB Life 2002, 54(6): 323-33.
35. Teerlink, J.R. A novel approach to improve cardiac performance: Cardiac
myosin activators. Heart Fail Rev 2009, 14(4): 289-98.
36. Solaro, R.J. CK-1827452, a sarcomere-directed cardiac myosin activator for
acute and chronic heart disease. IDrugs 2009, 12(4): 243-51.
37. Lee, K., Clarke, D., Hartman, J.J. et al. The fast skeletal troponin activator,
CK-1909178, increases skeletal muscle force in-vitro and in-situ. Biophys J
2009, 96(3, Suppl. 1): 231a.
38. Kawas, R., Russell, A., Rodriguez, H. et al. The small molecule skeletal sar-
comere activator, CK-1909178, is a calcium sensitizer that binds selectively
to the fast skeletal troponin complex. 54th Annu Meet Biophys Soc (Feb
20-24, San Francisco) 2010, Abst 778-Pos.
39. Ochala, J., Gokhin, D.S., Penisson-Besnier, I. et al. Congenital myopathy-
causing tropomyosin mutations induce thin filament dysfunction via dis-
tinct physiological mechanisms. Hum Mol Genet 2012, 21(20): 4473-85.
40. Russell, A.J., Lee, K., Jia, Z. et al. The fast skeletal troponin activator CK-
2017357 increases skeletal muscle force in vitro and in situ. FASEB J [Exp
Biol (April 18-22, New Orleans) 2009] 2009(Abstract Issue): Abst
600.13.
41. Russell, A.J., Hartman, J.J., Hinken, A.C. et al. Activation of fast skeletal
muscle troponin as a potential therapeutic approach for treating neuro-
muscular diseases. Nat Med 2012, 18(3): 452-5.
42. Kennedy, A.R., Heald, N., Pakdel, A. et al. he fast skeletal troponin activa-
tor, CK-2017357, improves resistance to fatigue in healthy, conscious rats.
Exp Biol (April 21-25, San Diego) 2012, Abst 1121.7.
43. Lindstrom, J.M., Engel, A.G., Seybold, M.E., Lennon, V.A., Lambert, E.H.
Pathological mechanisms in experimental autoimmune myasthenia gravis.
II. Passive transfer of experimental autoimmune myasthenia gravis in rats
with anti-acetylcholine recepotr antibodies. J Exp Med 1976, 144(3): 739-
53.
44. Mao, J., Vo, C.H., Xu, D., Bergnes, G., Morgan, B.P., Morgans, D.J. Cross-
species pharmacokinetics of CK-2017357, a novel activator of the fast skele-
tal sarcomere. 2010 FIP PSWC/AAPS Annu Meet Exp (Nov, New
Orleans), 2010, Poster presentation.
45. Mao, J., Chou, W., Malik, F. et al. Oral pharmacokinetics of CK-2017357 in
healthy subjects. 39th Annu Meet Am Coll Clin Pharmacol (ACCP) (Sept
12-14, Baltimore) 2010, Abst 68.
46. Shefner, J., Cedarbaum, J.M., Cudkowicz, M.E. et al. Safety, tolerability
and pharmacodynamics of a skeletal muscle activator in amyotrophic lat-
eral sclerosis. Amyotroph Lateral Scler 2012, 13(5): 430-8.
47. Chou, W., Hansen, R., Saikali, K.G. et al. CK-2017357, a novel activator of
fast skeletal muscle increases isometric force evoked by electrical stimula-
tion of the anterior tibialis muscle in healthy male subjects. 12th Int Congr
Neuromuscular Dis (July 17-22, Sao Paulo) 2010, Abst.
48. Shefner, J., Andrews, J., Bedlack, R. et al. A study to evaluate safety and
tolerability of CK-2017357 (CK-357) in patients with amyotrophic lateral
sclerosis using a twice-daily, dose-titration regimen. 64thAnnu Meet Am
Acad Neurol (AAN) (April 21-28, New Orleans) 2012, Abst P04.155.
49. Hiatt, W.R., Hirsch, A.T., Bauer, T.A. et al. Efficacy and tolerability of the
novel fast skeletal muscle troponin activator, CK-2017357, in patients with
claudication. 22nd Annu Sess Soc Vasc Med (June, Boston), 2011, Poster
presentation.
C
162
TIRASEMTIV M. Romano and E. Buratti
THOMSON REUTERS – Drugs of the Future 2013, 38(3)
