Discovery of omecamtiv mecarbil the first, selective, small molecule activator of cardiac myosin

Article abstract of DOI:10.1021/ml100138q

We report the design, synthesis, and optimization of the first, selective activators of cardiac myosin. Starting with a poorly soluble, nitro-aromatic hit compound (1), potent, selective, and soluble myosin activators were designed culminating in the discovery of omecamtiv mecarbil (24). Compound 24 is currently in clinical trials for the treatment of systolic heart failure.

Full text of DOI:10.1021/ml100138q

pubs.acs.org/acsmedchemlett
Discovery of Omecamtiv Mecarbil the First, Selective,
Small Molecule Activator of Cardiac Myosin
Bradley P. Morgan,* Alexander Muci, Pu-Ping Lu, Xiangping Qian, Todd Tochimoto,
Whitney W. Smith, Marc Garard, Erica Kraynack, Scott Collibee, Ion Suehiro,
Adam Tomasi, S. Corey Valdez, Wenyue Wang, Hong Jiang, James Hartman,
Hector M. Rodriguez, Raja Kawas, Sheila Sylvester, Kathleen A. Elias, Guillermo Godinez,
Kenneth Lee, Robert Anderson, Sandra Sueoka, Donghong Xu, Zhengping Wang,
Nebojsa Djordjevic, Fady I. Malik, and David J. Morgans, Jr.
Cytokinetics, Inc., 280 East Grand Avenue, South San Francisco, California 94080
ABSTRACT We report the design, synthesis, and optimization of the first,
selective activators of cardiac myosin. Starting with a poorly soluble, nitro-
aromatic hit compound (1), potent, selective, and soluble myosin activators were
designed culminating in the discovery of omecamtiv mecarbil (24). Compound 24 is
currently in clinical trials for the treatment of systolic heart failure.
KEYWORDS Omecamtiv mecarbil, small molecule enzyme activator, cardiac myo-
sin, systolic heart failure
strategy to treat systolic heart failure (HF) is to
increase cardiac contractility. Current drugs, such as
dobutamine, milrinone, and digoxin, activate second
A high-throughput screen (HTS) identified compound 1 as
a sarcomere activator having an AC40 value in the low
micromolar range. There were several interesting biological
characteristics of 1 that made this series of compounds
worthy of pursuit. First, 1 demonstrated excellent selectivity
for the cardiac sarcomere over the skeletal sarcomere and
smooth muscle myosin.9 Second, 1 demonstrated increased
contractility in freshly isolated, adult rat myocytes as mea-
sured by an increase in fractional shortening (FS).10 Impor-
tantly, no effects on the myocyte calcium transient were
observed. The degree of FS observed (ΔFS % = 135% at
2 μM) was substantial and was believed to be of sufficient
potency to elicit a biological response in a whole animal
at therapeutically relevant doses. However, the poor physical
properties of 1 did not allow this hypothesis to be tested
in vivo.
Although compound 1 was viewed as a promising lead
based on its interesting biological properties, 1 and various
analogs presented several formidable challenges to obtain
agents suitable for both acute iv administration and chronic
oral therapy. These challenges included an undesired struc-
tural moiety (nitro group), hydrolytic instability of the diaryl
amide, poor aqueous solubility, low free fraction, modest
intrinsic potency, off-target activities such as direct vasodila-
tion through KATP channel activity11 and CYP 1A2 inhibition,
and high intrinsic clearance. Our goal was to address these
challenges systematically while maintaining the favorable
properties for compound 1 such as selectivity for cardiac
A
messenger pathways that raise cardiac myocyte calcium
concentrations and subsequently increase cardiac contrac-
tility. Unfortunately, these drugs also increase heart rate and
myocardial oxygen consumption and can produce clinically
significant arrhythmias and hypotension, and their use is
associated with higher mortality.1,2
Our approach is to selectively increase cardiac contrac-
tility by exploiting a novel mechanism of action that directly
targets cardiac myosin, acting downstream of second mes-
senger activation and calcium regulation.3 Direct activation
of myosin, the molecular motor that drives muscle con-
traction, may avoid the mechanism-related toxicities of
current inotropes and offer a novel and potentially useful
treatment for HF.4 This report describes the discovery and
optimization program that led to selective activators of
the cardiac sarcomere culminating in the discovery of
omecamtiv mecarbil (24), a compound with the potential
to treat systolic HF in an acute situation through iv admin-
istration and acute and chronic systolic HF through oral
administration.
In the cardiac sarcomere, force generation is directly
coupled to adenosine triphosphate (ATP) hydrolysis. Com-
pounds that activate the cardiac sarcomere were identified
by measuring increases in myosin ATPase activity in a high-
throughput, fully soluble, calcium-responsive, reconstituted
sarcomere or myofibril assay.5-7 Data were reported as an
AC40, the compound concentration resulting in a 40%
increase in the cardiac sarcomere ATPase activity at the
calcium concentrations that produced 25-50% of maxi-
mum calcium-dependent activation.8
Received Date: June 11, 2010
Accepted Date: July 26, 2010
Published on Web Date: August 20, 2010
r
2010 American Chemical Society
472
DOI: 10.1021/ml100138q ACS Med. Chem. Lett. 2010, 1, 472–477
|

pubs.acs.org/acsmedchemlett
Scheme 1. General Synthesis of Aryl Ether Ureasa
Scheme 2. General Synthesis of Benzylpiperazine Ureasa
a Reagents and conditions: (a) NaH or K2CO3, R1OH, DMF, room
temperature-70 °C, 30-85%. (b) H2, Pd/C, MeOH, room temperature;
or Pd/C, NH4CO3, MeOH, reflux or SnCl2, EtOH, 50 f 95%. (c) Triphos-
gene, DIPEA, R2NH2, THF or CH2Cl2, room temperature, 60-85%.
myosin over other type II myosins, lack of effect on the
calcium transient or other off-target cellular effects, lack of
additional off-target effects as measured by general
screening,12 and good permeability.
a Reagents and conditions: X = Br or OMs; Y = F or H; R = methoxy-
carbonyl or t-butoxycarbonyl (t-Boc). When t-Boc was used as a
protecting group, it was converted to the methyl carbamate in the
following manner: (1) Trifluoroacetic acid, CH2Cl2, room temperature.
(2) Methyl chloroformate, DIPEA, THFor CH2Cl2, 0 °C. (a) NaHB(OAc)3,
CH2Cl2, room temperature. (b) H2, Pd/C, MeOH, room temperature.
(c) DIPEA, CH2Cl2, room temperature, 85%. (d) H2, Pd/C, K2CO3,
MeOH, room temperature, 80%. (e) Triphosgene, DIPEA, 2-methyl-5-
aminopyridine, THF or CH2Cl2, room temperature; or 2-methyl-5-
isocyanatopyridine, acetone, room temperature, 65-85%.
To achieve this goal, we designed flexible synthetic
routes to allow variation at each part of the molecule as
shown in Schemes 1 and 2. Nucleophilic aromatic substitu-
tion of nitroarene 15 (Scheme 1) with the appropriate
deprotonated hydroxypyridine or amino alcohol provided
nitro-substituted ether 16.13 The nitro group was reduced to
aniline 17 using standard protocols (e.g., H2, Pd/C, or Pd/C,
NH4CO3, or SnCl2). In situ generation of the isocyanate
of R2NH2 using 0.4 equiv of triphosgene and 2.1 equiv
of diisopropylethylamine (DIPEA),14 followed by reaction
with a substituted amino pyridine, afforded desired
analogues 4-14. Reductive amination15 of 18 with the
appropriately substituted benzaldehyde 19 (Scheme 2)
yielded desired benzyl piperazines 21 (after reduction of
the nitro moiety for R0 = NO2). Alternatively, 21 was
attained by alkylation of piperazine 18 with the benzyl
bromide or mesylate of the nitroaromatic compound 20
in the presence of DIPEA as base followed by reduction of
the nitro group as described above. Urea formation
as described above or by direct addition of the isocyanato-
pyridine to 21 furnished the desired ureas 22-24 in good
yield.
Table 1. HTS Hit (1) and Replacement of the Nitro Moiety
no.
X
AC40 (μM)
kinetic solubility (μg/mL)
1
2
3
-NO2
-F
1.4
2.5
32
<1.0
5.3
-H
17
The first level of optimization served to remove the
undesirable nitro group of 1 (Table 1). A first principle
driving this structure-activity relationship (SAR) was to
maintain an electron-withdrawing group at this position to
reduce the potential for oxidative metabolism of the pen-
dant aromatic ring. A fluorine atom replacement (2) main-
tained the biochemical activity of the parent nitro com-
pound. Hydrogen (3) substitution dramatically attenuated
the activity.
The next level ofoptimization addressed the low hydrolytic
stability of the diaryl amide moiety and the poor aqueous
solubility. Substitution of the amide of 2 with a more hydro-
lytically stable urea moiety16 (4) maintained biochemical
potency and gave measurable improvements in cardio-
myocte activity (Ta bl e 2 ). Substitution of the 4-fluoro moiety
on the terminal phenyl ring was tolerated as exemplified by
compounds 4 and 5; however, the compounds had poor
aqueous solubility. The addition of a nitrogen atom into the
terminal phenyl ring (6) began to improve solubility without
affecting biochemical or cellular potency. Removal of the
methoxy adjacent to the pyridine nitrogen of 6 to form the
more basic pyridine 7 resulted in additional modest improve-
ments in solubility without affecting biochemical or cellular
potency.
Compounds were periodically assessed for increases in FS
(ΔFS %)17 in normal rats using a bolus iv injection at typical
screening doses of 5 and 10 mg/kg to provide a yes/no
answer for in vivo activity. A common feature for all com-
pounds at this stage of optimization was high clearance in
rats. When high clearance is combined with a moderate
affinity for the target, binding to plasma protein generally
plays a role in in vivo potency.18 The relationship of plasma
protein binding19-22 versus the FS (in vivo) observed at bolus
r
2010 American Chemical Society
473
DOI: 10.1021/ml100138q ACS Med. Chem. Lett. 2010, 1, 472–477
|

pubs.acs.org/acsmedchemlett
Table 2. Improved Hydrolytic Stability and Modest Improvements in Solubilitya
no.
Y
A
Z
AC40 (μΜ)
CM (ΔFS % at μΜ)
KSol (μg/mL)
PB (% bound)
2
4
5
6
7
-NHCO-
CH
CH
CH
N
F
F
2.5
1.8
0.7
1.4
1.1
104 at 2.0
121 at 2.0
139 at 2.0
134 at 2.0
137 at 2.0
5.3
1.1
92.1
NA
-NHCONH-
-NHCONH-
-NHCONH-
-NHCONH-
OMe
OMe
H
<1.0
28
95.1
92.5
92.9
N
46
a CM, cardiomyocytes; KSol, kinetic solubility; and PB, plasma protein binding.
doses of 5 or 10 mg/kg for 20 compounds of similar
biochemical and cellular potencies is shown in Figure 1.
Compounds with ΔFS % < 120% in vivo span a range of
protein binding from approximately 80 to >95% with
several compounds clustering above the 90% bound. How-
ever, compounds with ΔFS % > 120% contain only the set
of molecules that have e90% of the drug bound to plasma
proteins.
Table 3 outlines representative compounds that demon-
strated reduced protein binding, removed off-target activ-
ities, improved cardiomyocyte potency, and improved
intrinsic clearance. Saturation of the “left-side” aryl ring
while maintaining an H-bond acceptor maintained good
biochemical and cellular potencies and reduced the protein
binding (8). CYP 1A2 inhibition was removed by sterically
blocking the “right-side” pyridyl nitrogen with an adjacent
methyl group (e.g., 8 versus 10).24,25 The vasodilatory
activity mediated through KATP channel opening26 was
very sensitive to the “left-side” moiety. For example, sub-
stitution of the pendant acetyl moiety of 8 as a carbamate
11 or N,N-dimethyl sulfonyl 12 attenuated direct vasodila-
tion, as measured by the aortic ring R50, and inverting the
stereochemistry of 8 to 9 removed any detectable vasodila-
tion. Additional “left-side” modifications resulted in re-
moval of any detectable vasodilation and improved
cardiomyocyte potency (8, 12, and 13). Modest improve-
ment in oxidative metabolism, as shown by the human
extraction ratio (Re) in microsomes, was observed by
shifting the connectivity of the piperidine ring to the
core phenyl substituent, thus removing the stereocenter
(11 vs 14).
With an understanding of how to remove the off-target
liabilities of our compounds, additional optimization fo-
cused on further reduction in oxidative turnover to improve
the in vivo pharmacokinetic (PK) parameters, imp-
roved solubility for the iv administration, and improved
potency in cardiomyocytes that should result in better dose
efficacy. As shown in Table 4, substitution of the O-linked
left side piperidine moiety of 14 with the methylene linked
piperazine ring of CK-1316189 (22) reduced the extraction
ratio in human microsomes, dramatically improved the
solubility, and improved cardiomyocyte potency. Unlike
Figure 1. Plasma protein binding (% bound HPLC) vsincreased FS
(ΔFS %) in vivo (rats) from an iv injection of test article where
measured ΔFS % > 120% is considered more active and ΔFS %
< 120% is less active.
the initial SAR, removal of the fluorine from the 5-position
of the central ring did not attenuate potency (23 versus 22).
Finally, reinstallation of the fluorine in the 2-position of the
central ring resulted in improved cardiomyocyte potency
with no measurable off-target liabilities (24). Introduction
of the basic nitrogen of the piperazine improved the
physical properties of the molecule (e.g., cLog P values:
14 = 3.0, and 24 = 1.4), and the weak basicity of this
nitrogen (pKa = 6.1) did not introduce additional off-target
interactions.
Improved cardiac contractility as measured by increased
FS in normal, Sprague-Dawley rats (Figure 2) confirmed
the desired effect of cardiac sarcomere activation on sys-
tolic function.27 Compounds 23 and 24 demonstrated
concentration-dependent increases in FS in this model.
r
2010 American Chemical Society
474
DOI: 10.1021/ml100138q ACS Med. Chem. Lett. 2010, 1, 472–477
|

pubs.acs.org/acsmedchemlett
Table 3. Reduction in Protein Binding, Removal of Off-Target Activities, Improvements in Cardiomyocyte Potency, and Improvements in
Intrinsic Clearancea
a CM, cardiomyocytes; Shake Sol, shake flask solubility; PB, plasma protein binding; Re, ratio of extraction in microsomes; and NA, not available.
Table 4. Additional Improvements in Oxidative Turnover, Increased Solubility, and Improved Potency in Cardiomyocytesa
AC40
(μM)
CM (ΔFS %
at μM)
Shake Sol
(mg/mL at pH 5)
PB
(% bound)
aortic ring
CYP 1A2
IC50 (μM)
human
Re
no.
X
W
R
50 (μM)
CK-1316189 (22)
F
H
H
F
1.7
131 at 0.8
138 at 0.8
123 at 0.2
4.6
4.0
2.2
89.7
87.2
79.6
>25
15
>10
>10
>10
<0.2
<0.2
<0.2
CK-1317138 (23)
H
H
4.5
omecamtiv mecarbil (24)
0.58
>25
a CM, cardiomyocytes; Shake Sol, shake flask solubility; PB, plasma protein binding; and Re, ratio of extraction in microsomes.
As expected from its improved in vitro potency and
greater free fraction, 24 showed greater potency in vivo
as compared to 23. In dog models of HF, 24 showed
increases in cardiac contractility as measured by increased
FS, increased stroke volume, and increased cardiac
output.28,29,30
As predicted from in vitro measures of drug metabo-
lism, 24 demonstrated good PK parameters in both
rats (Sprague-Dawley) and dogs (Beagle) with clearances
of 22 and 7.2 mL/min/kg, volumes of 3.5 and 3.6
L/kg, and bioavailabilities (F%) of 100 and 80%, respec-
tively.
In conclusion, omecamtiv mecarbil (24) is a potent, selec-
tive activator of cardiac myosin that leads to increases in
cardiac function in preclinical models of HF and now in
patients with HF due to systolic dysfunction.31 Its physical
and PK properties make 24 suitable for either intravenous or
oral administration. With the support of these results and
other promising data, 24 is currently in clinical trials for the
treatment of systolic HF.32
r
2010 American Chemical Society
475
DOI: 10.1021/ml100138q ACS Med. Chem. Lett. 2010, 1, 472–477
|

pubs.acs.org/acsmedchemlett
(6)
(7)
(8)
Hartman, J. J.; Malik, F.; Sakowicz, R.; Finer, J. T. High through-
put sarcomeric assay. U.S. Patent 6495337 B1, December 17,
2002; 12 pp.
Hartman, J. J.; Malik, F.; Sakowicz, R.; Finer, J. T. High through-
put sarcomeric assay. U.S. Patent 6509167 B1, January 21,
2003; 12 pp.
Select compounds were periodically examined using bovine,
rat, and human sources of an active cardiac myosin fragment
to assess variability across species. No difference in activity
was observed across species.
(9)
Compound specificity with respect to muscle type was
evaluated by comparing the effect of the compound on the
actin-stimulated ATPase activity of a panel of myosin iso-
forms [cardiac (bovine), skeletal (rabbit), and smooth muscle
(bovine uterus or chicken gizzard)] at a single dose of 40, 50,
or 100 μM compound. The data for compound 1 are shown in
Figure S1 in the Supporting Information.
(10) FS is the change in myocyte length divided by the resting
length of the cell. ΔFS is the percent change in FS after
treatment relative to FS at baseline, which is defined as 100%.
(11) Direct vasodilatation effects were measured by the ability of
compounds to relax a potassium chloride (KCl)- or a phenyl-
ephrine-induced contraction of a rat aortic ring. The vasodi-
latation effect of 8 in rat aortic rings was shown to be inde-
pendent of endothelium, protein kinase G, and protein kinase
A pathways for vascular relaxation. However, a dose-related
inhibition of the vasodilatation effect of 8 was observed when
the aortic ring preparations were pretreated with the KATP
channel inhibitor glybenclamide. Therefore, the vasodilata-
tion effect of 8 was determined to be due to its ability to
activate KATP channels.
Figure 2. Concentration-dependent increase in placebo-corrected
absolute fraction shortening in rats by CK-1317138 and omecamtiv
mecarbil. N=5-6 per data point. Points within the dashed lines were
significantly different from placebo (p < 0. 05).
SUPPORTING INFORMATION AVAILABLE Experimental
procedures and analytical data. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author: *To whom correspondence should be
addressed. Tel: 650-624-3003. Fax: 650-614-3010. E-mail: bmorgan@
cytokinetics.com.
(12) https://pharmacology.ricerca.com/Catalog/AssayCatalog/
AssayCatalog.aspx?path=128&leaf=128.
(13) Chen, N.; Hale, C; Karbon, W.; Norman, M. H. Synthesis and
structure-activity relationships of trisubstituted phenyl urea
derivatives as neuropeptide Y5 receptor antagonists. J. Med.
Chem. 2001, 44, 2344–2356.
ACKNOWLEDGMENT We thank all members of the much
larger Cardiovascular Program Team at Cytokinetics for their
contributions.
(14) Majer, P.; Randad, R. S. A Safe and Efficient Method for
Preparation of N,N0-Unsymmetrically Disubstituted Ureas
Utilizing Triphosgene. J. Org. Chem. 1994, 59, 1937–1938.
(15) Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff,
C. A.; Shah, R. D. Reductive Amination of Aldehydes and
Ketones with Sodium Triacetoxyborohydride. Studies on
Direct and Indirect Reductive Amination Procedures. J. Org.
Chem. 1996, 61, 3849–3862.
(16) Estiu, G.; Merz, K. M. The Hydrolysis of Amides and the
Proficiency of Amidohydrolases. The Burden Borne by kw.
J. Phys. Chem. B 2007, 111, 6507–6519 and references therein.
(17) FS, measured by echocardiographic imaging, is an assess-
ment of cardiac contractility. FS = (end diastolic diameter -
end systolic diameter)/end diastolic diameter ꢀ 100 as
determined by standard analysis of the M-mode images.
(18) Benet, L. Z.; Hoener, B. Changes in plasma protein binding
have little clinical relevance. Clin. Pharm. Ther. 2002, 71 (3),
115–121.
(19) Kim, H. S.; Mallic, R.; Hage, D. S. Chromatographic analysis of
carbamazepine binding to human serum albumin. II. Com-
parison of the Schiff base and N-hydroxysuccinimide immo-
bilization methods. J. Chromatogr. 2006, B837, 138–146 and
references therein.
(20) Hage, D. S. High-performance affinity chromatography:
A powerful tool for studying serum protein binding. J. Chro-
matogr. 2002, B768, 3–30.
ABBREVIATIONS ATP, adenosine triphosphate; DIPEA, di-
isopropylethylamine; PK, pharmacokinetic; SAR, structure-
activity relationship.
REFERENCES
(1)
Cohn, J. N.; Goldstein, S. O.; Greenberg, B. H.; Lorell, B. H.;
Bourge, R. C.; Jaski, B. E.; Gottlieb, S. O.; McGrew, F.; DeMets,
D. L.; White, B. G. A dose-dependent increase in mortality
with vesnarinone among patents with severe heart failure.
Vesnarinone Trial Investigators. N. Engl. J. Med. 1998, 339
(25), 1810–1816.
(2)
Packer, M.; Carver, J. R.; Rodeheffer, R. J.; Ivanhoe, R. J.;
DiBianco, R.; Zeldis, S. M.; Hendrix, G. H.; Bommer, W. J.;
Elkayam, U.; Kukin, M. L. Effect of oral milrinone on mortality
in severe chronic heart failure. The PROMISE Study Research
Group. N. Engl. J. Med. 1991, 325 (21), 1468–1475.
Spirito, P.; Seidman, C. E.; McKenna, W. J.; Maron, B. J. The
management of hypertrophic cardiomyopathy. N. Engl. J.
Med. 1997, 336 (11), 775–785.
Teerlink, J. R. A novel approach to improve cardiac perfor-
mance: cardiac myosin activators. Heart Failure Rev. 2009,
14, 289–298 and references therein.
Finer, J. T.; Malik, F.; Sakowicz, R.; Shumate, C.; Wood, K.
Compositions and assays utilizing ADP or phosphate for
detecting protein modulators. U.S. Patent 6410254 B1, June
25, 2002; 13 pp.
(3)
(4)
(5)
(21) Noctor, T. A.; Pham, C. D.; Kaliszan, R.; Wainer, I. W. Stereo-
chemical aspects of benzodiazepine binding to human serum
r
2010 American Chemical Society
476
DOI: 10.1021/ml100138q ACS Med. Chem. Lett. 2010, 1, 472–477
|

pubs.acs.org/acsmedchemlett
albumin. I. Enantioselective high performance liquid affinity
chromatographic examination of chiral and achiral bind-
ing interactions between 1,4-benzodiazepines and human
serum albumin. Mol. Pharmacol. 1992, 42, 506–511.
(22) Kim, H. S.; Hage, D. S. Chromatographic analysis of carba-
mazepine binding to human serum albumin. J. Chromatogr.
2005, B816, 57–66.
(23) Obach, R. S. Prediction of human clearance of twenty-nine
drugs from hepatic microsomal intrinsic clearance data: An
examination of in vitro half-life approach and nonspecific
binding to microsomes. Drug Metab. Dispos. 1999, 27, 1350–
1359.
(24) Bromidge, S. M.; Duckworth, M.; Forbes, I. T.; Ham, P.; King,
F. D.; Thewlas, K. M.; Blaney, F. E.; Naylor, C. B.; Blackburn,
T. P.; Kennett, G. A.; Wood, M. D.; Clarke, S. E. 6-Chloro-5-
methyl-1-[[2-[(2-methyl-3-pyridyl)oxy]-5-pyridyl]carbamoyl]-
indoline (SB-242084): The first selective and brain penetrant
5-HT2C receptor antagonist. J. Med. Chem. 1997, 40, 3494–
3496.
(25) Bromidge, S. M.; Dabbs, S.; Davies, D. T.; Davies, S.; Duckworth,
M.; Forbes, I. T.; Gaster, L. M.; Ham, P.; Jones, G. E.; King, F. D.;
Mulholland, K. R.; Saunders, D. V.; Wyman, P. A.; Blaney,
F. E.; Clarke, S. E.; Blackburn, T. P.; Holland, V.; Kennett, G. A.;
Lightowler, S.; Middlemiss, D. N.; Trail, B.; Riley, G. J.; Wood,
M. D. Biarylcarbamoylindolines Are Novel and Selective
5-HT2C Receptor Inverse Agonists: Identification of 5-Methyl-
1-[[2-[(2-methyl-3-pyridyl)oxy]- 5-pyridyl]carbamoyl]-6-trifluoro-
methylindoline (SB-243213) as a Potential Antidepressant/
Anxiolytic Agent. J. Med. Chem. 2000, 43, 1123–1134.
(26) Measured by the concentration at which a compound ex-
hibited a 50% relaxation to baseline levels of a precontracted
rat aortic ring (R50 in Table 3).
(27) Anderson, R. L.; Sueoka, S. H.; Rodriguez, H. M.; Lee, K. H.;
Cox, D. R.; Kawas, R.; Morgan, B. P.; Sakowicz, R.; Morgans,
D. J., Jr.; Malik, F.; Elias, K. A. In Vitro and In Vivo Efficacy of
the Cardiac Myosin Activator CK-1827452. American Society
of Cell Biology (ASCB), December, 2005.
(28) Shen, Y.; Zhang, Y.; Morgans, D. J.; Vatner, S. F.; Malik, F. A
Novel Inotropic Agent That Activates Cardiac Myosin and
Increases Cardiac Contractility Without Increasing MVO2 in
Heart Failure with Left Ventricular Hypertrophy. American
College of Cardiology Conference, Chicago, IL, March, 2008.
(29) Malik, F.; Elias, K. A.; Finer, J. T.; Morgan, B. P.; Sakowicz, R.;
Anderson, R.; Baliga, R.; Conn, L.; Cox, D.; Garard, M.;
Hartman, J;. Irvine, J.; Kawas, R.; Kraynack, E.; Kuklov, A.;
Lee, K. H.; Lu, P.; Muci, A.; Pierce, D. W.; Rodriguez, H.;
Suehiro, I.; Sueoka, S. H.; Sylvester, S.; Tochimoto, T.; Valdez,
C.; Wang, W.; Katori, T.; Kass, D. A.; Shen, Y. T.; Vatner, S. F.;
Morgans, D. J. Direct Activation of Cardiac Myosin by CK-
1827452 Improves Cardiac Function in a Dog Heart Failure
Model. Heart Failure Society of America Meeting, September,
2005.
(30) Shen, Y. T.; Malik, F. I; Zhao, X.; Depre, C.; Dhar, S. K.;
ꢀ
Abarzua, P.; Morgans, D. J.; Vatner, S. F. Improvement of
Cardiac Function by a Cardiac Myosin Activator in Conscious
Dogs with Systolic Heart Failure. Circulation: Heart Failure, 2010,
3 (4), 522–527.
(31) Senior, R.; Malik, F. I.; Saikali, K. G.; Lee, J. H.; Chen, M. M.;
Brand, G.; Wolff, A. A., and the CY 1121 Investigators. The
Selective Cardiac Myosin Activator, CK-1827452, Increases
Systolic Function in a Concentration Dependent Manner in
Patients with Sable Heart Failure. Annual American College of
Cardiology (ACC), Orlando, FL, March 2009.
(32) http://clinicaltrials.gov.
r
2010 American Chemical Society
477
DOI: 10.1021/ml100138q ACS Med. Chem. Lett. 2010, 1, 472–477
|