Discovery of GSK2798745: A Clinical Candidate for Inhibition of Transient Receptor Potential Vanilloid 4 (TRPV4)

Article abstract of DOI:10.1021/acsmedchemlett.9b00274

GSK2798745, a clinical candidate, was identified as an inhibitor of the transient receptor potential vanilloid 4 (TRPV4) ion channel for the treatment of pulmonary edema associated with congestive heart failure. We discuss the lead optimization of this novel spirocarbamate series and specifically focus on our strategies and solutions for achieving desirable potency, rat pharmacokinetics, and physicochemical properties. We highlight the use of conformational bias to deliver potency and optimization of volume of distribution and unbound clearance to enable desirable in vivo mean residence times.

Full text of DOI:10.1021/acsmedchemlett.9b00274

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Letter
Discovery of GSK2798745: A Clinical Candidate for the
Inhibition of Transient Receptor Potential Vanilloid 4 (TRPV4)
Carl A. Brooks, Linda S. Barton, David J Behm, Hilary Schenck Eidam, Ryan M Fox, Marlys Hammond,
Tram H. Hoang, Dennis A. Holt, Mark Alan Hilfiker, Brian G. Lawhorn, Jaclyn R Patterson, Patrick Stoy,
Theresa J Roethke, Guosen Ye, Steve Zhao, Kevin S. Thorneloe, Krista Beaver Goodman, and Mui Cheung
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.9b00274 • Publication Date (Web): 15 Jul 2019
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Discovery of GSK2798745: A Clinical Candidate for the Inhibition of
Transient Receptor Potential Vanilloid 4 (TRPV4)
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Carl A. Brooks*, Linda S. Barton, David J. Behm, Hilary S. Eidam, Ryan M. Fox, Marlys Hammond,
Tram H. Hoang, Dennis A. Holt, Mark A. Hilfiker, Brian G. Lawhorn, Jaclyn R. Patterson, Patrick Stoy,
Theresa J. Roethke, Guosen Ye, Steve Zhao, Kevin S. Thorneloe, Krista B. Goodman, Mui Cheung
GlaxoSmithKline, Heart Failure Discovery Performance Unit, Metabolic Pathways and Cardiovascular Therapeutic Area, 1250
S Collegeville Road, Collegeville, Pennsylvania, 19426, United States.
KEYWORDS GSK2798745, TRPV4, congestive heart failure, conformational bias, volume of distribution
ABSTRACT: GSK2798745, a clinical candidate was identified as an inhibitor of the Transient Receptor Potential Vanilloid 4
(TRPV4) ion channel for the treatment of pulmonary edema associated with congestive heart failure. We discuss the lead optimization
of this novel spirocarbamate series specifically focusing on our strategies and solutions for achieving desirable potency, rat
pharmacokinetics and physicochemical properties. We highlight the use of conformational bias to deliver potency and optimization
of volume of distribution and unbound clearance to enable desirable in vivo mean residence times.
Transient receptor potential vanilloid 4 (TRPV4) is a cation
channel that mediates the influx of Ca2+ across plasma
membranes.1 The channel can be activated by heat,
hypotonicity, physical stress and small molecules.2-5 TRPV4
activation caused by heightened pulmonary vascular pressure
increases permeability of the alveolar septal barrier that leads to
pulmonary edema.6-7
robust oral bioavailability (>30 %) and mean residence time
(MRT). An extended MRT is highly desirable as it minimizes
the peak to trough concentrations during a dose which improves
therapeutic index and enables a lower overall dose. A minimum
MRT of two hours in rat was projected to scale to enable once
a day dosing in human.11, 12
In addition to the potency and PK targets we sought to identify
a compound with desirable physicochemical properties to
mitigate selectivity and attrition liabilities.13-14 Thus, we
targeted compounds exhibiting a cLogP of <3.5 and measured
chromatographic logD at pH 7.4 (ChromLogD) of <4.0.13
In pre-clinical congestive heart failure models, increased
pressure in the pulmonary vascular system causes the
development of pulmonary edema, which is reduced with
TRPV4 channel inhibition. Therefore, a TRPV4 inhibitor is
hypothesized to prevent channel activation and reduce
pulmonary edema in heart failure patients.8-9
Figure 1. Spirocarbamate lead
hTRPV4 IC50a = 16 ± 2.5 nM
GSK previoulsy reported TRPV4 anatagonists series,
quinolines and benzimidazoles, failed to deliver clinical drug
candidates necessitating the need to identify an alternative
series.10,19
a
rTRPV4 IC50 = 5.5 ± 1.5 nM
O
N
ChromLogD = 4.5
O
cLogP = 4.2
Herein we report the discovery of GSK2798745 (30) a clinical
candidate for the inhibition of TRPV4. GSK2798745 (30) arose
from a lead optimization campaign aimed at identifying a small
molecule oral drug candidate capable of inhibiting the TRPV4
ion channel at or above unbound IC50 for 24 hours per day from
a low once a day oral dose.
Rat PKb,c
MRTiv = 0.7 h
N
CLiv = 64 mL/min/kg
N
Vdssiv = 2.6 L/Kg
Fpo = 63%
N
To achieve this target profile, we optimized the molecule for
both potency and pharmacokinetics (PK). TRPV4 inhibition
was measured via a FLIPR HEK cellular assay with a targeted
IC50 ≤ 10 nM required for successful candidates. PK
optimization was performed in Sprague Dawley rats.10 We
focused our attention on identification of compounds with
rPPB fu = 32%
rCLu = 200 mL/min/kg
1
aTRPV4 IC50 are an average of at least two measurements.
bDMPK properties are an average of measurements taken in at
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least two Sprague-Dawley rats. cRat PPB fu are an average of at
Page 2 of 8
potency offered by the methyl group (~2 kcal/mol) is beyond
that of lipophilic binding energy, as indicated by LLE increase
(1 = 3.4, 3 = 4.7), and is suggestive of a conformational effect,
perhaps reducing the conformational flexibility of the
cyclohexane or benzimdazole.23,24
1
2
3
4
5
6
7
8
least two measurements
The spirocarbamate lead 1 (Figure 1) was derived from an HTS
screening hit molecule from the GSK screening collection.15
Compound 1 demonstrated robust potency against TRPV4 (IC50
= 16 nM) and an attractive physicochemical properties starting
Compound 4 was designed to address potential oxidation near
the carbamate nitrogen through substitution of the neopentyl
group with tert-butyl but had no benefit on MRT (0.5 h) and
demonstrated weak TRPV4 potency (IC50 = 5,200 nM). In
contrast, N-Aryl substitution (5) provided a significant increase
in both MRT (3.1 h) and oral bioavailability (100%).
point, with a ChromLogD = 4.5 and LLE = 3.4 (LLE = pIC50
–
ChromLogD), especially compared to earlier reported TRPV4
inhibitors.10,16-19
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The initial focus of our lead optimization effort was to improve
the rat PK of 1 which demonstrated a short MRT (0.7 h). MRT
is the quotient of volume of distribution (Vdss) and clearance
(CL).12,20 It can thus be extended by either increased Vdss or
reduced clearance. Our initial strategy was to address the high
in vivo clearance (64 mL/min/kg) of 1 by removing metabolic
liabilities.
The increased MRT of 5 is a result of both reduced clearance
and more importantly increased Vdss. The 3-fold clearance
reduction can be fully attributed to a 5-fold increase in plasma
protein binding for 5 (fu = 6.5 %) compared to 1 (fu = 32%). The
unbound clearance (CLu = CL/PPB fu, 1 = 200, 5 = 350)
indicates that there is minimal change in the free drug clearance
between the N-neopentyl (1) and N-aryl (6). In contrast, the
volume of distribution increase is very substantial. The 5-fold
increase in PPB fu between the N-neopentyl (1) and N-aryl (5)
would have been expected to elicit a proportional reduction in
the Vdss.24 Instead, we observed a 1.5-fold increase in Vdss. This
indicates that the unbound drug volume of distribution (Vdss/fu,
1 = 8.1, 5 = 61) has increased by eight times and is the
underlying driver for the increased MRT. The Vdss increase
cannot be attributed to any change in lipophilicity with
ChromLogD remaining unchanged at 4.5. Unfortunately, the
aryl substitution producing 5 led to a substantial loss in TRPV4
potency compared to 1 (IC50 = 1,900 nM vs 16 nM).
Oxidation adjacent to nitrogen is a well-documented pathway
of metabolism and was observed in an in-vitro metabolism ID
study.21 To address potential sites of metabolism in 1, we
targeted four analogs (2-5) specifically aimed at sterically
blocking oxidative metabolism (Table 1).22
Table 1. Initial analogs to address clearance
F
O
O
O
O
N
N
N
O
O
N
O
O
N
N
N
N
N
N
N
N
Table 2. N-aryl potency SAR on the 5 desmethylcyclohexane
core.
N
N
N
N
+/-
+/-
+/-
O
Cmpd
2
3
4
5
N
R
O
hTRPV4
>25,0
00
±0
0.5
±0.03
5,200
±710
1,900
±610
IC50 ± SEM
(nM)a
N
N
Ch.LogD
cLogP
4.6
4.9
4.6
4.7
4.0
3.6
4.5
3.7
N
Rat PKb
MRTiv (h)
CLiv
0.3
70
0.5
63
0.5
55
3.1
23
hTRPV4
IC50 ±SEM
Cmpd
R
ChromLogD
(nM)a
(mL/min/kg
)
p-F (±)
H
1,900 ± 610
820 ± 200
140 ± 7.9
74 ± 11
5
6
4.5
4.6
4.8
5.0
5.3
4.3
4.2
4.6
4.2
Vdiv (L/kg)
Fpo
rPPB fu
1.1
8%
--
2.1
32%
14%
450
1.8
44%
--
4.0
100%
6.5 %
350
c
7
p-OEt
m-OEt
m-Cl
o-Cl
CLu
--
--
(mL/min/k
g)
8
aTRPV4 IC50 are an average of at least two measurements. .
bDMPK properties are an average of measurements taken in at
least two Sprague-Dawley rats. cRat PPB fu are an average of at
least two measurements
240 ± 51
63 ± 2.9
9
10
11
12
13
540 ± 150
310 ± 29
340 ± 85
o-F
o-Me
o-OMe
Installing a gemdimethyl group adjacent to the benzimidazole
nitrogen (2) had no benefit on MRT (0.3 h) and reduced TRPV4
activity significantly (IC50 > 25,000 nM). An alternative
approach to sterically block metabolism at the methylene center
through methyl introduction onto the cyclohexane ring (3)
similarly had no benefit on MRT (0.5 h). Interestingly, we noted
a profound 32-fold TRPV4 potency increase resulting from this
change (IC50 = 0.5 nM) over compound 1. The enhanced
aTRPV4 IC50 are an average of at least two measurements
Initial attempts to address the potency loss of 5 via N-aryl
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substitutions led to multiple analogs that improved potency by
O
1
~10 fold (7-10), but did not meet the 10 nM target.
N
R
O
2
3
4
5
6
7
8
9
This led us to incorporate the potency-enhancing methyl
observed in 3 into the cyclohexane ring of 5 to give 14. This
modification led to the expected improvement in potency (IC50
= 96 nM) and the excellent rat PK was maintained (Figure 2).
Based on its improved potency, we were optimistic that 14
could be improved to reach the target potency at TRPV4 (IC50
< 10 nM) by leveraging the established N-aryl substituent SAR
(Table 2).
N
N
N
hTRPV4
IC50
Me
Chrom
LogDb
Cmpd
R
LLE Effect
10
11
12
13
14
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±SEM
c
Figure 2. Early methyl-cyclohexane N-aryl analog
(nM)a
F
96 ± 17
49 ± 5.9
5.2 ± 0.3
1.6 ± 0.2
48 ± 7.5
2.5 ± 0.3
5.2 ± 1.0
1.7 ± 0.2
1.2 ± 0.2
14
15
16
17
18
19
20
21
22
p-F
H
4.9
5.0
5.4
5.3
5.7
4.8
4.9
4.8
4.6
2.1
2.3
2.9
3.5
1.6
3.8
3.4
4.0
4.3
20x
17x
26x
45x
5x
hTRPV4 IC50a = 96 ± 17 nM
O
N
ChromLogD = 4.9
cLogP = 4.1
O
p-OEt
m-OEt
m-Cl
o-Cl
Rat PKb
N
MRTiv = 2.8 h
CLiv = 39 mL/min/kg
Vdssiv = 6.5 L/kg
Fpo = 100%
N
N
25x
100x
200x
280x
14
aTRPV4 IC50 are an average of at least two measurements.
bDMPK properties are an average of measurements taken in at
least two Sprague-Dawley rats.
o-F
o-Me
o-OMe
The combination of N-aryl substituents with the
methylcyclohexane core led to many highly potent (<10 nM)
compounds (Table 3) but also highlighted that highly divergent
SAR existed between the desmethylcyclohexane and
methylcyclohexane cores. Para- and meta-ethoxy substitution
(16 and 17) demonstrated excellent potency (IC50 = 5.2 and 1.6
nM) which can be attributed to the potency of corresponding
desmethylcyclohexane analogs 7 & 8 (IC50 = 140 & 74 nM)
which is supplemented by the expected ~30-fold potency
increase from the methylcyclohexane core. Meta-chloro
substitution (18) demonstrated 50 nM potency and the minimal
aTRPV4 IC50 are an average of at least two measurements. bLLE
= TRPV4 pIC50 – ChromLogD. Methyl effect is the fold
change in hTRPV4 IC50 for the corresponding analogs in table
2.
c
Unfortunately, the introduction of the potency enhancing
alkoxy groups led to reduced MRT’s by differing mechanisms
as exemplified by 16 and 22 (Table 4). The reduced MRT of 22
(1.0 h) is the result of reduced volume of distribution (1.4 L/kg)
with clearance (26 mL/min/kg) remaining similar to para-
fluoro 14 (39 mL/min/kg). Apparently, the potency enhancing
conformational effect of the ortho-methoxy substituent (22) led
to reduced tissue affinity versus 14, which would be difficult to
correct while maintaining potency. In contrast, the reduced
MRT of 16 (0.9 h) is a function of increased clearance (140
mL/min/kg) with volume of distribution remaining unchanged
(7.2 L/kg) relative to para-fluoro 14 (6.5 L/kg). The para-
ethoxy group presumably introduced a metabolic liability, but
without changing the underlying volume of distribution
advantage observed with the early N-aryls 5 and 14.
and
unexpected
5-fold
potency
increase
over
desmethylcyclohexane 6 revealed that divergent SAR existed
between the two structurally similar cores. The disparate SAR
was most apparent in compounds bearing ortho-aryl
substituents (11-14). Ortho-substituted compounds on the
desmethylcyclohexane core (10-13) typically had minimal
effects on potency. However, installing the methylcyclohexane
core on these ortho-substituted analogs produced activity
increases of up to 280x to give compounds such as 22 with
TRPV4 IC50 = 1.2 nM. We noted that the efficiency for the
methylcyclohexane core introduction with ortho-substituents
also correlated with increased electron donating capacity of the
substituent. (σpara Cl = +0.23, F = +0.06, Me = -0.17, OMe = -
0.27). We hypothesized that electron donating ortho-
substituents elicit a strong conformational effect on the N-aryl
rotation which is highly complementary to the conformational
Table 4. Potent N-aryl compounds with reduced MRTs
O
effects elicited by the methylcyclohexane core.21,23-24
.
Of
O
O
interest, the compound containing a meta-Cl (18) substituent
exhibited a much higher measured lipophilicity (ChromLogD =
5.7) compared to the ortho-Cl (19) analog (ChromLogd = 4.8),
which may arise from the proposed N-aryl conformational
effects caused by the ortho-substituents.
N
N
O
O
O
N
N
N
N
N
N
Cmpd
16
22
Table 3. N-aryl methylcyclohexane TRPV4 potency SAR
3
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eliminated by pyridyl nitrogen insertion. We hypothesized that
hTRPV4 IC50
±
5.2 ± 0.3
1.2 ± 0.2
1
2
3
4
5
6
7
8
the nitrogen containing heterocycles may be reducing
metabolism either through reduced cytochrome P450 binding
affinity or by reducing aryl oxidative capacity.26
SEM (nM)a
ChromLogD
cLogP
Rat PKb
MRTiv (h)
CLiv
5.4
4.5
4.6
4.0
Figured 3. A potent TRPV4 inhibitor with desirable rat PK
0.9
140
1.0
26
hTRPV4 IC50a = 4.2 ± 0.5 nM
O
(mL/min/kg)
Vdiv (L/kg)
Fpo
N
O
7.2
29 %
--
1.4
100 %
3.6 %
720
ChromLogD = 5.5
N
9
N
cLogP = 3.1
O
c
10
11
12
13
14
15
16
17
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22
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25
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50
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53
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57
58
59
60
rPPB fu
Rat PKb,c
CLu
(mL/min/kg)
--
MRTiv = 5.2 h
aTRPV4 IC50 are an average of at least two measurements.
bDMPK properties are an average of measurements taken in two
Sprague-Dawley rats. cRat PPB fu are an average of at least two
measurements.
N
CLiv = 17 mL/min/kg
Vdssiv = 5.4 L/kg
Fpo = 100%
N
N
rPPB fu = 3.7%
rCLu = 460 mL/min/kg
25
aTRPV4 IC50 are an average of at least two measurements.
bDMPK properties are an average of measurements taken in two
Sprague-Dawley rats. cRat PPB fu are an average of at least two
measurements.
Consistent with this conclusion, we could reduce clearance and
restore the MRT of 16 via the introduction of heterocycles (23-
25) which are thought to attenuate oxidative metabolism of the
aryl ring (Table 5).26
Having established our target TRPV4 potency and rat PK in
compounds such as 25 (Figure 3) we also noted that the
replacement of phenyl (16) with pyrazine (25) dramatically
lowered cLogP from 4.5 to 3.1. Therefore, we progressed 25 to
candidate selection, but it was subsequently surpassed by a
superior compound, which resulted from lowering measured
lipophilicity.
Table 5. Rat PK SAR for pyridyl and diazine analogs
O
R
N
O
N
N
Interestingly, the pyrazine had no effect on measured
lipophilicity as ChromLogD was nearly identical for 16 (5.4)
and 25 (5.5). We sought to reduce the measured lipophilicity
recognizing that this value is more relevant for positively
impacting off-target activity and solubility.14 Specifically for
this series we had noted that the unbound clearance of 25 was
inferior to 1 and 5 both of which demonstrated lower
ChromLogD. We hypothesized that by decreasing lipophilicity
we could reduce unbound clearance, presumably through
attenuating binding affinity to metabolizing enzymes. An
improvement in unbound clearance while maintaining potency
and MRT is highly desirable as it leads to increased free drug
concentration that lowers the overall clinical dose.27
N
hTRPV4
IC50
rCLiv
(mL/mi
n/kg)b
PPB
fu
MR
T
Cmpd
R
+SEM
(%)c
(h)b
(nM)a
O
--
5.2 ± 0.3
3.1 ± 0.5
60 + 15
16
23
24
25
140
24
0.9
1.6
1.9
5.2
O
O
O
3.1
--
N
14
N
N
N
4.2 ± 0.5
17
3.7
N
aTRPV4 IC50 are an average of at least two measurements.
bDMPK properties are an average of measurements taken in two
Sprague-Dawley rats. cRat PPB fu are an average of at least two
measurements.
Table 6. Aryl substituent lipophilicity SAR
O
R
N
O
The 2-ethoxy pyridyl (23) improved potency (IC50 = 3.1 nM),
lowered clearance (24 mL/min/kg) and enhanced MRT (1.6 h)
versus 16, prompting efforts to incorporate an additional
nitrogen to produce alkoxy diazines. Ethoxy pyridazine (24) led
to a further reduction in clearance (14 mL/min/kg) and increase
in MRT (1.9 h), but also reduced the TRPV4 potency (IC50 = 60
nM). In contrast, the ethoxy pyrazine (25) demonstrated robust
TRPV4 potency (IC50 = 4.2 nM) and a long MRT (5.2 h) but
with similar clearance (17 mL/min/kg) to 23 and 24. Overall
our conclusion is that para-ethoxy substitution (16) enhanced
or introduced arene oxidation and that this can be attenuated or
N
N
N
hTRPV4
b,c
IC50
±
Cmpd
16
R
Ch.LogD
rCLu
SEM(nM)a
O
5.2 ± 0.3
5.4
--
4
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bDMPK properties are an average of measurements taken in two
O
N
4.2 ± 0.5
25
5.5
460
Sprague-Dawley rats. cRat PPB fu are an average of at least two
measurements
1
N
2
3
4
5
O
N
26
27
14 ± 1.6
60 ± 1.8
4.8
4.2
400
--
N
Overall, compound 30 demonstrated excellent TRPV4 potency,
owing largely to the methyl-cyclohexane core, and showed
exceptional rat PK. The long MRT (4.9 h) and low unbound
clearance (81) could be attributed to the metabolic stability of
the N-aryl pyrazine and low overall lipophilicity of the
compound. Compound 30 (designated GSK2798745)
demonstrated efficacy in an in vivo rat PK/PD model of
pulmonary edema, excellent TRP selectivity (M5, A1, C3 and
C6 > 25 µM) and an adequate preclinical safety profile that
enabled its candidate selection and subsequent progression to
clinical trials.9,29
N
N
6
7
8
9
N
N
1.5 ± 0.2
1.2 ± 0.3
28
29
5.3
6.3
340
--
N
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
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46
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50
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N
OH
1.8 ± 0.2
30
4.0
79
N
aTRPV4 IC50 are an average of at least two measurements. .
bDMPK properties are an average of measurements taken in two
Sprague-Dawley rats. cRat PPB fu are an average of at least two
measurements. CLu = CL x PPB fu
The spirocarbamate TRPV4 inhibitors were accessed via the
synthetic method described in supplemental data Schemes 1
and 2.30
In summary, a lead optimization effort beginning with
spirocarbamate 1 identified GSK2798745 (30), a clinical
candidate for the inhibition of TRPV4. The lead optimization
began by successfully addressing the poor rat PK of the lead but
resulted in a significant reduction in TRPV4 potency. The
TRPV4 potency loss was addressed primarily through the
introduction of a highly efficient methyl group. This was then
followed by subtle refinement of TRPV4 potency, rat
pharmacokinetics and physiochemical properties to achieve a
desirable oral candidate profile. GSK2798745 is a clinical
candidate that is being used to assess the role of TRPV4 in
human diseases.
We modulated lipophilicity by varying the pyrazine substituent
of 25 (Table 6). Contraction from ethoxy (25) to methoxy (26)
reduced ChromLogD (5.5 to 4.8) and CLu (460 to 400) but at
the expense of potency (IC50 = 14 nM). Exchange of ethoxy for
a methyl substituent (27) reduced ChromLogD to 4.2 but again
led to modest TRPV4 potency (IC50 = 60 nM). Target potency
could be increased through larger alkyl groups such as cyclo-
propyl (28) and tert-butyl (29) to 1.5 nM and 1.2 nM
respectively, with the former demonstrating slightly improved
CLu relative to 25. The alkyl substituent data (27-29) illustrated
the importance of lipophilicity for obtaining excellent TRPV4
potency, but also demonstrated that a potency/lipophilicity
plateau had been reached since 29 gave no activity increase over
28. The latter observation led us to replace one of tert-butyl
methyls in 29 with a hydroxy group to give isopropyl alcohol
(30) which demonstrated excellent TRPV4 potency (IC50 = 1.8
nM) along with significantly reduced ChromLogD (4.0). The
reduced lipophilicity led to a six fold improvement in CLu
compared to 25. We hypothesize that the hydroxy may be
internally hydrogen-bonded to the adjacent pyrazine nitrogen
when bound to TRPV4, thereby masking some its polarity
leading to the excellent potency. However, the polarity of the
hydroxy group is apparently dynamically exposed in aqueous
solvent leading to its reduced ChromLogD and unbound
clearance.28
ASSOCIATED CONTENT
Supporting Information.
Compound synthesis and
spectroscopic characterization of 1, 16, 25 and 30. This
material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
* E-mail: carl.a.brooks@gsk.com
Present Addresses
1250 S Collegeville Road, Collegeville, PA, 19426
Author Contributions
All authors have given approval to the final version of the
manuscript.
Figure 4. GSK2798745 TRPV4 oral candidate
Funding Sources
hTRPV4 IC50a = 1.8 ± 0.2 nM
The authors declare the following competing financial interests:
All authors are current or past employees of GlaxoSmithKline
and/or stockholders of GlaxoSmithKline.
rTRPV4 IC50a = 1.6 ± 0.2 nM
OH
N
O
N
ChromLogD = 4.0
N
O
cLogP = 1.3
NOTES
All studies involving the use of animals were conducted after
review by the GlaxoSmithKline (GSK) Institutional Animal
Care and Use Committee and in accordance with the GSK
Policy on the Care, Welfare and Treatment of Laboratory
Animals.
Rat PKb,c
MRTiv = 4.9 h
N
CLiv = 6.5 mL/min/kg
Vdssiv = 1.9 L/kg
Fpo = 59%
N
N
30
rPPB fu = 8.2%
ACKNOWLEDGMENT
rCLu = 79 mL/min/kg
aTRPV4 IC50 are an average of at least two measurements.
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T. J.; Jucker, B. M.; Schnackenberg, C. G.; Townsley, M. I.;
We thank all members of the TRPV4 Program Team at
GlaxoSmithKline for their contribution. We thank Remy Gebleux
and Lina Ding for synthetic contributions. J.P Jarworski and
Michael Klein for TRPV4 FLIPR data; Katrina Rivera, Stephen
Eisennagel and Kevin Baptiste for rat PK data.
Lepore, J. J.; Willette, R. N. An Orally Active TRPV4
Channel Blocker Prevents and Resolves Pulmonary Edema
Induced by Heart Failure. Sci. Transl. Med., 2012, 4,
159ra148.
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ABBREVIATIONS
ChromLogD, chromatographic logD at pH 7.4; cmpd, compound;
CL, clearance; CLu, clearance of unbound drug, FLIPR,
fluorometric imaging plate reader; IV, intravenous; Fpo, oral
bioavailability; MRT, mean residence time; PK, pharmacokinetic;
PPB Fu, plasma protein binding fraction unbound; SAR, structure-
activity relationship; TRPV, transient receptor potential vanilloid;
Vdss, volume of distribution at steady state;
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aromaticity. Drug discovery today, Vol 16, Numbers 17/18 pp
822-830, 2011.
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