Discovery of MK-7145, an Oral Small Molecule ROMK Inhibitor for the Treatment of Hypertension and Heart Failure

Article abstract of DOI:10.1021/acsmedchemlett.6b00122

ROMK, the renal outer medullary potassium channel, is involved in potassium recycling at the thick ascending loop of Henle and potassium secretion at the cortical collecting duct in the kidney nephron. Because of this dual site of action, selective inhibitors of ROMK are expected to represent a new class of diuretics/natriuretics with superior efficacy and reduced urinary loss of potassium compared to standard-of-care loop and thiazide diuretics. Following our earlier work, this communication will detail subsequent medicinal chemistry endeavors to further improve lead selectivity against the hERG channel and preclinical pharmacokinetic properties. Pharmacological assessment of highlighted inhibitors will be described, including pharmacodynamic studies in both an acute rat diuresis/natriuresis model and a subchronic blood pressure model in spontaneous hypertensive rats. These proof-of-biology studies established for the first time that the human and rodent genetics accurately predict the in vivo pharmacology of ROMK inhibitors and supported identification of the first small molecule ROMK inhibitor clinical candidate, MK-7145.

Full text of DOI:10.1021/acsmedchemlett.6b00122

Letter
pubs.acs.org/acsmedchemlett
Discovery of MK-7145, an Oral Small Molecule ROMK Inhibitor for
the Treatment of Hypertension and Heart Failure
Haifeng Tang,*,† Yuping Zhu,† Nardos Teumelsan,† Shawn P. Walsh,† Aurash Shahripour,†
Birgit T. Priest,‡ Andrew M. Swensen,‡ John P. Felix,‡ Richard M. Brochu,‡ Timothy Bailey,‡
Brande Thomas-Fowlkes,‡ Lee-Yuh Pai,§ Caryn Hampton,§ Aaron Corona,§ Melba Hernandez,§
Joseph Metzger,§ Michael Forrest,§ Xiaoyan Zhou,∥ Karen Owens,⊥ Vincent Tong,⊥ Emma Parmee,†
Sophie Roy,∥ Gregory J. Kaczorowski,‡ Lihu Yang,† Magdalena Alonso-Galicia,∥ Maria L. Garcia,‡
and Alexander Pasternak†
‡
§
∥
⊥
†Departments of Discovery Chemistry, Ion Channels, In Vivo Pharmacology, Cardiorenal, and Pharmacokinetics,
Pharmacodynamics and Drug Metabolism, Merck Research Laboratories, Kenilworth, New Jersey 07033, United States
S
* Supporting Information
ABSTRACT: ROMK, the renal outer medullary potassium channel, is involved in potassium recycling at the thick ascending
loop of Henle and potassium secretion at the cortical collecting duct in the kidney nephron. Because of this dual site of action,
selective inhibitors of ROMK are expected to represent a new class of diuretics/natriuretics with superior efficacy and reduced
urinary loss of potassium compared to standard-of-care loop and thiazide diuretics. Following our earlier work, this
communication will detail subsequent medicinal chemistry endeavors to further improve lead selectivity against the hERG
channel and preclinical pharmacokinetic properties. Pharmacological assessment of highlighted inhibitors will be described,
including pharmacodynamic studies in both an acute rat diuresis/natriuresis model and a subchronic blood pressure model in
spontaneous hypertensive rats. These proof-of-biology studies established for the first time that the human and rodent genetics
accurately predict the in vivo pharmacology of ROMK inhibitors and supported identification of the first small molecule ROMK
inhibitor clinical candidate, MK-7145.
KEYWORDS: ROMK, diuretics, natriuresis, hypertension, heart failure, MK-7145
for further understanding of ROMK pharmacology, which may
he renal outer medullary potassium channel (ROMK,
Tencoded by the KCNJ1 gene) is an inward rectifying ultimately lead to development of a new class of diuretics for
the treatment of hypertension and edematous states such as
heart failure.10
potassium channel (Kir1.1) that plays a key role in renal salt
recycling and potassium homeostasis.1,2 In the kidney nephron,
ROMK is expressed at both the thick ascending loop of Henle
(TALH) and the cortical collecting duct (CCD).3 At the
TALH, ROMK facilitates potassium recycling across the
luminal membrane, which is critical for the proper function
of the furosemide-sensitive Na+/K+/2Cl− cotransporter. At the
CCD, ROMK is involved in potassium secretion that is tightly
coupled to sodium uptake through the amiloride-sensitive
epithelial sodium channel (ENaC).4,5 This dual site of function
suggests that ROMK inhibitors may provide superior diuretic/
natriuretic efficacy with reduced urinary loss of potassium
compared to standard-of-care loop and thiazide diuretics. This
hypothesis is supported by a growing body of evidence in both
human6,7 and rodent8,9 genetics. However, the human
pharmacology of ROMK is unexplored largely due to lack of
selective ROMK inhibitors. Thus, suitable inhibitors are needed
Recently, we have disclosed the development of a new class
of small molecule ROMK inhibitors exemplified by compound
1.11 Although compound 1 was shown to display diuretic and
natriuretic activity, when dosed orally in animals, it features
somewhat high clearance rates across three preclinical species
with a relatively low exposure and short half-life (Table 1). The
major metabolite observed from a bile duct cannulated rat
study (>parent in urine and primary component in bile) and
from in vitro incubation in human and rat microsomes and liver
S9 fractions was the hydrolyzed lactone, with comparable
stability seen from rat and human microsomes and liver S9
Received: March 20, 2016
Accepted: May 12, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acsmedchemlett.6b00122
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Letter
about 1000-fold selectivity over hERG. Thus, 5 was assessed in
a rat pharmacokinetic study and shown to still display high
clearance and a short half-life.
Table 1. Pharmacokinetic Properties of Compound 1 (dose,
1 mg/kg IV, 2 mg/kg PO; n = 3)
In a parallel SAR effort, the phthalide pharmacophore was
introduced into our previously described piperazine diamine
series (Figure 2).18 Compared to the original lead compound 6,
compound 718 retained similar ROMK inhibitory potency.
While compound 6 is 7-fold selective for hERG, compound 7
displays 21-fold selectivity for ROMK. Further incorporation of
4-methyl phthalide led to compound 8, with similar ROMK
potency and marginally improved hERG selectivity. Next, as
described in the piperazine carboxamide series, one α-hydroxyl
group was added to furnish compound 9. Interestingly,
racemate 9 showed a small improvement in ROMK activity
and a decrease in hERG potency, resulting in a significant
overall improvement in hERG selectivity. Importantly, hERG
selectivity could be improved an additional 4-fold when the
symmetric diol 10 was synthesized. When the isomer mixture
10 was evaluated in the ROMK and hERG electrophysiology
(EP) assays,13 potency and selectivity were even more
remarkable (ROMK EP IC50 0.015 μM, hERG EP IC50 28
μM; hERG EP/ROMK EP = 1870). The diol 10 was further
converted into the corresponding difluoro analogue 11, which
showed reduced ROMK potency compared to compound 10 in
both the 86Rb+ efflux and EP assays, and reduced potency in
35S-MK499 binding and hERG EP assays.19 To further
differentiate 10 and 11, the isomeric mixtures of both
compounds were evaluated in an acute Sprague−Dawley
(SD) rat diuresis model.20 Diol 10 demonstrated remarkable
diuresis and natriuresis at either 3 or 10 mg/kg oral dosing. In
comparison, 11 showed significant but modest efficacy only at
10 mg/kg (Table 2), probably due to its weaker ROMK
inhibitory activity, as well as lower compound levels in urine as
compared to 10.21 Thus, further efforts were devoted to
prepare and profile stereoisomers of diol 10.
species
rat
40
dog
Rhesus
Cl (mL/min/kg)
Vdss (L/kg)
AUCNpo (μM·h·kg/mg)
half-life (h)
36
34
0.66
0.34
0.62
33
1.9
0.88
1.4
80
1.4
0.12
1.1
11
F%
fractions. Based on the short half-lives in preclinical species and
comparable metabolism profile in human microsomes and liver
S9 fractions, it is unlikely that compound 1 would have a
human half-life consistent with once daily dosing. In addition,
despite its 100-fold selectivity against hERG, QTc prolongation
(i.e., >5% increase over vehicle control) was observed when 1
was evaluated in an anesthetized and vagotomized cardiovas-
cular dog model.12 Thus, significant improvement in hERG
selectivity, with an improved PK profile, would be required in
order to identify a small molecule clinical candidate ROMK
inhibitor.
Unless otherwise noted, the ROMK inhibitory activity of
compounds was initially assessed in a 86Rb+ efflux functional
assay,13 whereas hERG inhibition was determined in a 35S-
MK499 radioligand binding assay.14 Initial structure−activity
relationship (SAR) work on the phthalide phenyl ring revealed
that substitution at the 4-position of the phthalide is tolerated.
For instance, the 4-methyl analogue (2)11 showed comparable
ROMK potency and hERG selectivity to 1 (Figure 1).15
Interestingly, a further improvement in hERG selectivity was
observed when a benzylic methyl was introduced to 2 (see
compound 3). Given these data, we decided to synthesize the
α-F analogue hoping for an improvement in hERG selectivity
while retaining ROMK activity. This expectation is based on
the idea that fluoride would reduce basicity of the piperizine
nitrogen and help to diminish the extent of hERG
inhibition.16,17 Fluoride 5 was accessed via alcohol 4. Notably,
although some loss of ROMK potency was observed for 4, we
did observe weaker hERG inhibition. Encouragingly, the fluoro
analogue 5 retained similar ROMK potency and demonstrated
Although it is possible to resolve the isomers of 10 by chiral
HPLC, it is much more efficient to prepare them via the chiral
epoxides. Heating of piperazine with either the R or S epoxide
gave rise to the R,R or S,S enantiomer, 12 and 13 (Figure 3).22
The meso-isomer can be prepared by stepwise epoxide opening
reactions. The R-epoxide was treated with 1-Boc piperazine to
furnish 14, which was followed by deprotection of Boc under
acidic conditions. Subsequent reaction of the revealed amine
(15) with the S-epoxide gave rise to the meso-isomer 16.
In the ROMK 86Rb+ efflux and EP assays, the three isomers
showed very similar potency, although their potency is
Figure 1. α-Substitution in the piperazine carboxamide series.
B
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Figure 2. α-Substitution in the piperazine diamine series (ROMK and hERG IC50 values determined in 86Rb+ efflux and 35S-MK499 binding assays,
respectively, unless otherwise indicated; EP, electrophysiology).
Table 2. Acute (4 h) Diuresis/Natriuresis of 10 and 11 in SD
Rat after Oral Dosing
Table 3. ROMK and hERG Activity of Stereoisomers of 10
(in μM)
a
b
b
compd
dose
diuresis fold increase
natriuresis fold increase
compd
12
13
16
c
c
10
10
11
11
3 mg/kg
10 mg/kg
3 mg/kg
6.7
9.4
ROMK 86Rb+ efflux
ROMK Tl+ flux
ROMK EP
0.068
0.006
0.009
23
0.134
0.059
0.012
47
0.112
0.010
0.009
100
c
c
6.8
9.5
1.6
1.7
c
c
10 mg/kg
3.0
3.0
hERG binding
hERG EP
a
b
c
22
22
>30
n = 5 per group. Compared to vehicle. p < 0.05 vs. vehicle.
hERG EP/ROMK EP
2440
1800
>3000
Table 4. Rat PK Properties of Compounds 12, 13, and 16
compd
12
13
16
dose IV/PO (mg/kg)
Cl (mL/min/kg)
Vdss (L/kg)
1/2
56
0.5/1
82
0.5/1
54
3.8
0.14
1.1
21
5.8
4.5
AUCNpo (μM·h·kg/mg)
half-life (h)
0.13
0.86
45
0.30
1.4
F%
44
Table 5. Acute (4 h) Diuresis/Natriuresis of Isomers of 10 in
a
SD Rat after Oral Dosing
diuresis fold
b
natriuresis fold
kaliuresis fold
b
b
compd
dose
increase
increase
increase
d
d
c
12
12
12
12
13
13
13
16
16
0.3 mg/kg
1 mg/kg
3 mg/kg
10 mg/kg
0.3 mg/kg
1 mg/kg
3 mg/kg
1 mg/kg
3 mg/kg
6.4
6.2
2.1
d
d
8.6
8.6
1.8
1.4
1.7
1.1
1.0
0.9
1.3
d
d
Figure 3. Synthesis of stereoisomers of 10.
9.0
8.0
d
d
9.4
8.5
1.3
1.6
1.9
1.4
1.5
2.2
significantly higher in the EP as compared to the 86Rb+ efflux
assay. All three isomers are weak inhibitors of the hERG
channel in both the 35S-MK499 binding and hERG EP assays.
In fact, all three isomers are at least 1800-fold selective for
ROMK in the EP assays. In a third type of ROMK functional
assay based on Tl+ influx,13 where compounds’ potencies
display a good correlation with the EP assay, the S,S-isomer 13
seemed to be 10-fold less potent than the R,R-isomer 12, while
the meso-isomer 16 showed similar potency to the R,R-isomer
(Table 3).
All three isomers were tested in rat pharmacokinetic studies,
showing similar oral exposure and half-lives (Table 4).
Surprisingly, quite different efficacies were observed when
dosed in the acute rat diuresis assay (Table 5). The R,R-isomer
12 evoked remarkable diuresis and natriuresis at doses as low as
0.3 mg/kg PO, while the S,S-isomer 13 did not display
d
d
3.5
3.7
d
d
4.5
4.1
1.1
a
b
c
d
n = 5 per group. Compared to vehicle. p < 0.01 vs. vehicle. p <
0.05 vs. vehicle.
significant activity at any of the tested doses.23 In comparison,
moderate efficacy was observed when the meso-isomer 16 was
tested at 1 and 3 mg/kg PO. Potassium excretion was increased
approximately 2-fold in animals that received HCTZ and 1.4- to
2.1-fold for those that received compound 12, but the latter
effect was not dose-dependent and was not significantly
different relative to vehicle treated animals for the 1, 3, and
10 mg/kg treatment groups. Moreover, the ratio of potassium
C
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to sodium excretion was lower for all three ROMK inhibitors
compared to HCTZ. Based on these results, the R,R-isomer 12
was selected for further profiling.24
Compound 12 was further dosed in dog and rhesus to assess
higher species pharmacokinetic properties (Table 6). Dog PK
periods at 1, 2, and 7 mg/kg (10 mg/kg cumulative dose) to
determine its effects on cardiovascular function in anesthetized
and vagotomized dogs. Heart rate, mean arterial pressure, and
electrocardiographic parameters (PR, QRS, and QT/QTc
intervals) were monitored predose and during each infusion
period. No treatment-related effects were observed during the
course of the experiment at plasma concentrations of up to 11.6
μM, illustrating the fact that cardiovascular risks of ROMK
inhibitors, such as 1, can be mitigated by enhancing their
selectivity against the hERG channel.
With a safe and efficacious compound in hand, 12 was tested
in a subchronic blood pressure study in spontaneously
hypertensive rats (SHR). The compound was dosed once
daily (QD) via oral gavage for 4 days, and changes in blood
pressure were monitored by implanted C40 telemetry devices.
As shown in Table 7, compound 12 evoked dose-dependent
Table 6. Dog and Rhesus PK Properties of Compound 12 (1
mpk IV, 2 mpk PO)
species
dog
Rhesus
Cl (mL/min/kg)
Vdss (L/kg)
AUCNpo (μM·h·kg/mg)
half-life (h)
56
29
7.5
0.32
1.7
51
6.7
0.30
4.0
25
F%
of 12 indicated a high clearance rate, which led to relatively
short half-life and low exposure. Compared to 1 (Table 1),
compound 12 in rhesus did show significant improvement in
half-life, benefiting mainly from a larger volume of distribution.
Table 7. Changes in SBP at Day 4 in SHR Dosed with
Compound 12
compd/dose
(mg/kg/day)
baseline
(mmHg)
SBP @ day 4
(mmHg)
ΔSBP @ day 4
3
In a bile duct cannulated rat study with H-12, the major
(mmHg)
clearance mechanisms were oxidative metabolism (by
CYP3A4) and urinary excretion of unchanged parent; minor
metabolism pathways included glucuronidation and lactone
hydrolysis. The major circulating component was parent.
vehicle
12/1
194 6.1
191 5.3
194 4.5
193 5.3
194 4.5
191 6.9
182 5.0
182 4.9
173 3.6
179 4.6
−2.5 2.2
−9.4 1.8
−12.4 0.7
−19.9 2.9
−15.0 2.1
12/3
12/10
HCTZ/25
3
Incubation of H-12 (1 μM) in rat, dog, monkey, and human
hepatocytes resulted in 15−37% turnover at 120 min with
oxidation products observed. In addition to the Phase 1
metabolites, the lactone hydrolysis product and the parent
glucuronide were also detected at very low levels (each <1%).
There were no human-specific metabolites. The projected
human half-life of compound 12 was estimated to be
approximately 5 h based upon a combination of in vitro to in
vivo correlation and allometric scaling, averaged from preclinical
species. Overall, compound 12 has moderately improved
pharmacokinetic properties and significantly improved pharma-
codynamic properties at lower doses and has better hERG
selectivity relative to compound 1.
decreases in systolic blood pressure (SBP) at day 4.26 At 3 mg/
kg/day of 12, the magnitude of SBP lowering (∼12 mmHg)
was similar to that achieved with hydrochlorothiazide (HCTZ)
(25 mg/kg/day).27 At 10 mg/kg/day, the SBP lowering efficacy
(∼20 mmHg) exceeded that of HCTZ at 25 mg/kg/day. To
the best of our knowledge, this is the first time that a small
molecule ROMK inhibitor has been used in an animal model to
show a blood pressure lowering effect. Based on its potency,
selectivity, safety, and superior in vivo efficacy, compound 12
was selected as a clinical development compound and
designated as MK-7145.
Compound 12 was screened against other members of the
Kir family of channels. It did not show any significant activity
on Kir2.1, Kir2.3, Kir4.1, or Kir7.1 channels when tested at
concentrations up to 30 μM. Compound 12 is also selective
against other cardiac ion channels such as Cav1.2 and Nav1.5
(IC50 > 30 μM). In addition, 12 was not a potent reversible
inhibitor of human CYP3A4, CYP2C9, or CYP2D6 (IC50 > 50
μM) and was not a time-dependent inhibitor of CYP3A4 at 10
and 50 μM. In a broad counterscreen panel conducted at
Panlabs and including over 150 receptors, enzymes, and ion
channels, 12 only exhibited three activities at <10 μM: acetyl
cholinesterase, ACES, IC50 = 9.94 μM, somatostatin subtype 1,
sst1 IC50 = 2.63 μM, and human serotonin transporter, SERT,
IC50 = 0.12 μM. The sst1 activity of 12 was followed up with
functional assays, and no functional activity was observed. In a
functional assay using HEK293 cells stably transfected with
human SERT, uptake of 3H-serotonin was inhibited by 12 with
an IC50 value of 2.40 0.32 μM (n = 5). The superior ROMK
potency and in vivo efficacy of 12, coupled with the fact that the
compound is a substrate of human Pgp (human Mdr1 BAAB
ratio = 12), should be able to impart a significant safety window
with respect to the SERT off-target activity.25
In summary, a new subseries of novel ROMK inhibitors were
developed by combining SAR information from the piperazine
carboxamide series and piperazine diamine series.28 Compared
to compound 1, diol 12 demonstrated much improved hERG
selectivity and did not display cardiac liabilities in a subsequent
assessment in a cardiovascular dog model. In addition,
compound 12 has moderately improved PK properties in
preclinical species. In the acute rat diuresis model, 12 evoked
remarkable diuresis and natriuresis at doses as low as 0.3 mg/
kg. For the first time with a small molecule ROMK inhibitor,
we were also able to show that compound 12 caused dose-
dependent lowering of blood pressure in a subchronic SHR
model. Following extensive profiling, 12 was selected as MK-
7145, the first small molecule ROMK inhibitor to enter clinical
development. Human data from clinical trials conducted with
MK-7145 will be reported in future publications.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acsmedchem-
lett.6b00122.
■
S
Finally, the cardiovascular safety of 12 was assessed in the
Merck cardiovascular dog model. The compound was
administered intravenously during three sequential 30 min
Synthesis of key compounds and characterization,
protocols of animal models, and discussions on
D
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Garcia, M. L.; Pasternak, A. Discovery of a novel sub-class of ROMK
channel inhibitors typified by 5-(2-(4-(2-(4-(1H-Tetrazol-1-yl)-
phenyl)acetyl)piperazin-1-yl)ethyl)-isobenzofuran-1(3H)-one. Bioorg.
Med. Chem. Lett. 2013, 23 (21), 5829−5832.
(12) The CV dog model was a Merck internal model used to assess
cardiovascular safety of research compounds.
compound hERG activity, ROMK PD efficacy in acute
rat diuresis model, and derisking off-target activity for
compound 12 (PDF)
AUTHOR INFORMATION
■
(13) Felix, J. P.; Priest, B. T.; Solly, S.; Bailey, T.; Brochu, R. M.; Liu,
C. J.; Kohler, M. G.; Kiss, L.; Alonso-Galicia, M.; Tang, H.; Pasternak,
A.; Kaczorowski, G. J.; Garcia, M. L. The inwardly rectifying potassium
channel Kir1.1: development of functional assays to identify and
characterize channel inhibitors. Assay Drug Dev. Technol. 2012, 10, 417.
(14) Wang, J.; Della Penna, K.; Wang, H.; Karczewski, J.; Connolly,
T. M.; Koblan, K. S.; Bennett, P. B.; Salata, J. J. Functional and
pharmacological properties of canine ERG potassium channels. Am. J.
Physiol. Heart Circ. Physiol. 2003, 284 (1), H256−267.
(15) The substitution SAR on the phthalide ring was thoroughly
explored, and only small substituents at the C-4 position afforded
compounds with similar ROMK potency and selectivity over hERG.
(16) Bell, I. M.; Bilodeau, M. T. The Impact of Ikr Blockade on
Medicinal Chemistry Programs. Curr. Top. Med. Chem. 2008, 8 (13),
1128−1139.
(17) For a recent review on the role of fluorine in medicinal
chemistry, please see: Gillis, E. P.; Eastman, K. J.; Hill, M. D.;
Donnelly, D. J.; Meanwell, N. A. Applications of Fluorine in Medicinal
Chemistry. J. Med. Chem. 2015, 58 (21), 8315−8359.
(18) Tang, H.; Walsh, S. P.; Yan, Y.; de Jesus, R. K.; Shahripour, A.;
Teumelsan, N.; Zhu, Y.; Ha, S.; Owens, K. A.; Thomas-Fowlkes, B. S.;
Felix, J. P.; Liu, J.; Kohler, M.; Priest, B. T.; Bailey, T.; Brochu, R.;
Alonso-Galicia, M.; Kaczorowski, G. J.; Roy, S.; Yang, L.; Mills, S. G.;
Garcia, M. L.; Pasternak, A. Discovery of Selective Small Molecule
ROMK Inhibitors as Potential New Mechanism Diuretics. ACS Med.
Chem. Lett. 2012, 3 (5), 367−372.
(19) The improvement of hERG off-target activity can be rationalized
by lowering of pKa and compound lipophilicity. Please see the
Supporting Information for correlation of hERG selectivity with
calculated pKa and LogD.
(20) Compounds 10 and 11 showed similar rat PK properties as
mixture of isomers.
(21) Please see the Supporting Information for further discussion on
ROMK PD efficacy of compounds 10 and 11.
(22) Please see the Supporting Information for preparation of both
chiral epoxides.
(23) Please see the Supporting Information for further discussion on
ROMK PD efficacy of compounds 12, 13, and 16.
(24) Despite of good efficacy in the acute rat diuresis model, meso-
isomer 16 showed quite low aqueous solubility based on qualitative
assessment. In comparison, R,R-isomer 12 has aqueous solubility of at
least 1 mg/mL.
Corresponding Author
*Tel: 908-740 4932. E-mail: haifeng_tang@merck.com.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Junling Gao and Dr. Li-Kang Zhang for help with
HR−MS analysis of key compounds.
ABBREVIATIONS
■
ROMK, renal outer medullary potassium channel; hERG, the
Human Ether-a-go-go-Related Gene; PK, pharmacokinetics;
PD, pharmacodynamics; EP, electrophysiology; SHR, sponta-
neous hypertensive rat; HCTZ, hydrochlorothiazide; QD, once
daily; PO, oral dosing
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Wang, W.; Giebisch, G.; Shull, G. E.; Hebert, S. C. Absence of Small
Conductance K+ Channel (SK) Activity in Apical Membranes of Thick
Ascending Limb and Cortical Collecting Duck in ROMK (Bartter’s)
Knockout Mice. J. Biol. Chem. 2002, 277 (40), 37881−37887.
(10) Lifton, R. P.; Gharavi, A. G.; Geller, D. S. Molecular
Mechanisms of Human Hypertension. Cell 2001, 104 (4), 545−556.
(11) Tang, H.; de Jesus, R. K.; Walsh, S. P.; Zhu, Y.; Yan, Y.; Priest,
B. T.; Swensen, A. M.; Alonso-Galicia, M.; Felix, J. P.; Brochu, R. M.;
Bailey, T.; Thomas-Fowlkes, B.; Zhou, X.; Pai, L.-Y.; Hampton, C.;
Hernandez, M.; Owens, K.; Roy, S.; Kaczorowski, G. J.; Yang, L.;
(25) Please see Supporting Information for detailed discussion on
derisking of hSERT off-target activity.
(26) Only changes in SBP at day 4 are disclosed in this
communication. For a more thorough description of the in vivo
pharmacology of compound 12, a manuscript by Caryn Hampton et al.
will be separately submitted for publication.
(27) Based on internal dose titration, HCTZ achieves approximately
the maximum blood pressure lowering efficacy in SHR at 25 mg/kg
oral dosing QD.
(28) For more SAR work on this end, please see: Walsh, S. P.;
Shahripour, A.; Tang, H.; Teumelsan, N.; Frie, J.; Zhu, Y.; Priest, B. T.;
Swensen, A. M.; Liu, J.; Margulis, M.; Visconti, R.; Weinglass, A.; Felix,
J. P.; Brochu, R. M.; Bailey, T.; Thomas-Fowlkes, B.; Alonso-Galicia,
M.; Zhou, X.; Pai, L.-Y.; Corona, A.; Hampton, C.; Hernandez, M.;
Bentley, R.; Chen, J.; Shah, K.; Metzger, J.; Forrest, M.; Owens, K.;
Tong, V.; Ha, S.; Roy, S.; Kaczorowski, G. J.; Yang, L.; Parmee, E.;
Garcia, M. L.; Sullivan, K.; Pasternak, A. Discovery of Selective Small
Molecule ROMK Inhibitors as Potential New Mechanism Diuretics.
ACS Med. Chem. Lett. 2015, 6 (7), 747−752 It is worth noting that
most of the SAR work in the mentioned publication was done after the
discovery of MK-7145..
E
DOI: 10.1021/acsmedchemlett.6b00122
ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX