Macitentan – A novel sulfamide Macitentan Bosentan Bolli M, et al. J Med Chem 2012; 55:7849-61.
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Transcript of Macitentan – A novel sulfamide Macitentan Bosentan Bolli M, et al. J Med Chem 2012; 55:7849-61.
N
N
NHS
O
O
OH
O
O O
N
N
N
N
NHS
NH
O
O
O O
N
N
Br
Br
Macitentan – A novel sulfamide
MacitentanBosentan
Bolli M, et al. J Med Chem 2012; 55:7849-61.
Tissue penetration requires drugs to cross from the bloodstream through the lipophilic cell membrane
• The ability of a drug to cross the bilipid membrane depends on
– Ionisation properties - drugs cross the membrane in the non-ionised, lipophilic form1
– Affinity for the lipid vs the aqueous phase1
– Size of the molecule1
1. Rowland M and Tozer TN. Clinical Pharmacokinetics: Concepts and applications. Lippincott Williams & Wilkins, 1995.
Optimisation of the physicochemical properties compared to Bosentan may favour macitentan’s penetration into tissues: pKa
A higher pKa corresponds to greater lipophilicity and thus greater tissue targeting potential
Adapted from Iglarz M, et al. J Pharmacol Exp Ther 2008; 327:736-45. pKa: ionisation dissociation constant
Optimisation of the physicochemical properties compared to Bosentan may favour macitentan’s penetration into tissues: Log D
Macitentan800:1
Bosentan20:1
Ambrisentan1:2.5
Blood
Tissue
Membrane
Log D (Distribution coefficient)
Lipid:Aqueous
• The distribution coefficient (Log D) defines the distribution of a compound between an aqueous and a lipid phase
• A greater affinity for the lipid phase may favour tissue penetration
• Macitentan may have a greater affinity for the lipid phase compared with other ERAs*
Iglarz M, et al. J Pharmacol Exp Ther 2008; 327:736-45.
In vitro data
*To date, no head-to-head trials in humans have been performed.
Macitentan displays sustained binding to its target receptors
Experimental system: Determination of changes in inhibitory potency after antagonist wash-out (calcium flux in PASMC)
Macitentan displays a 15-fold increased receptor residence time (t1/2) compared to ambrisentan and bosentan
*p < 0.05
* * * *
*
**
Bosentan
0.1
Kb a
fter
was
ho
ut
(nM
)
1
10
100
1000
0 20 40 60
t1/2~70 sec
0 20 40 60
**
* * *
*
*
Ambrisentan
t1/2~40 sec
Time after wash-out (minutes)
Time after wash-out (minutes)
*
*
*
Macitentan
6040200
t1/2~17 min
Time after wash-out (minutes)
In vitro data
Gatfield J, et al. PloS One 2012; 7(10):e47662.
In contrast to ambrisentan and bosentan, macitentan remains potent at elevated ET-1 concentrations
Experimental system: ET-1-induced signalling in human PASMCs measuring IP1
ET-1 concentration-response curves in presence of different concentrations of antagonists
XProtection against
high ET-1
Bosentan
10000 nM1000 nM100 nM10 nM1 nM0 nM
No
rma
lise
d I
P1
con
c. (
%)
0
20
40
60
80
100
120
-11 -10 -9 -8 -7 -6 -5ET-1 (log M)
20 nM 3000 nM InactiveIC50
xx x
X
Ambrisentan
-11 -10 -9 -8 -7 -6 -5ET-1 (log M)
2 nM 500 nM Inactive
x
x x
Macitentan
-11 -10 -9 -8 -7 -6 -5ET-1 (log M)
1 nM 5 nM 5 nM
x
x x
In vitro data
Gatfield J, et al. PloS One 2012; 7(10):e47662.
Chronic† macitentan administration reduced mPAP at a dose 10-fold lower than bosentan in the MCT rat model
Iglarz M, et al. J Pharmacol Exp Ther 2008; 327:736-45.†Administered for 4 weeks
MCT + bosentan
MCT + macitentan
MCT (monocrotaline)
Control
Veh 0.3 3 10 30 100 300
Dose (mg/kg/day)
40
30
20
10
mP
AP
(m
mH
g)
+++
*
*****
***
*** ***
***
+++ p < 0.001 vs. control
** p < 0.01 vs. MCT + vehicle
* p < 0.05 vs. MCT + vehicle
*** p < 0.001 vs. MCT + vehicle
Animal model
Chronic† macitentan administration reduced RV hypertrophy at a dose 10-fold lower than bosentan in the MCT rat model
Iglarz M, et al. J Pharmacol Exp Ther 2008; 327:736-45.RV: right ventricular†Administered for 4 weeks
MCT + bosentan
MCT + macitentan
MCT (monocrotaline)
Control
+++ p < 0.001 vs. control
** p < 0.01 vs. MCT + vehicle
* p < 0.05 vs. MCT + vehicle
*** p < 0.001 vs. MCT + vehicle
Veh 0.3 3 10 30 100 300
Dose (mg/kg/day)
0.5
0.4
0.3
0.2
RV
/LV
+S
Animal model
+++
*** **
*********
Effect of macitentan on survival in the MCT rat model of PAH
00
20
40
60
80
100
Su
rviv
al (
%)
7 14 21 28 35 42
Time (days)
Control
Monocrotaline (MCT) + vehicle
50%
*macitentan was administered at 30 mg/kg/day
MCT + macitentan*
83%
p = 0.002
Animal model
Iglarz M, et al. J Pharmacol Exp Ther 2008; 327:736-45.Raja SG. Curr Opin Investig Drugs 2010;11:1066-73.
Macitentan added to ambrisentan leads to a further reduction in MAP
**p < 0.05 vs. Ambrisentan then vehicle
Ambrisentanthen
vehicle
Ambrisentanthen
Macitentan
-50
-40
-30
-20
-10
0
Del
ta M
AP
(m
mH
g)
**
Ambrisentanthen
Ambrisentan
p = ns
Animal model
Dahl-S rats (n = 5), telemetry equippedDose: 30 mg/kg (ambrisentan or macitentan) by gavage Iglarz M, et al. Eur Respir J 2012; 40: Suppl. 56:717s.
Addition of ambrisentan to macitentan did not lead to further reductions in MAP
Dahl-S rats (n = 5), telemetry equippedDose: 30 mg/kg (ambrisentan or macitentan) by gavage
Macitentanthen
vehicle
Macitentanthen
Ambrisentan
-50
-40
-30
-20
-10
0D
elta
MA
P (
mm
Hg)
p = ns
Animal model
Iglarz M, et al. Eur Respir J 2012; 40: Suppl. 56:717s.
Macitentan added to bosentan leads to a further reduction in MAP
-50
-40
-30
-20
-10
0D
elta
MA
P (
mm
Hg)
Bosentanthen
vehicle
Bosentanthen
macitentan
Bosentanthen
bosentan
Dahl-Salt rat model of systemic hypertension (n = 4 to 9)Measurements in conscious animals (telemetry)Dose (by gavage): bosentan 100 mg/kg; macitentan 30 mg/kg
p = ns
**
Animal model **p < 0.05 vs. Bosentan then vehicle
Iglarz M, et al. Eur Respir J 2012; 40: Suppl. 56:717s.
Addition of bosentan to macitentan did not lead to further reductions in MAP
Macitentanthen
vehicle
Macitentanthen
bosentan
-50
-40
-30
-20
-10
0
Animal model
p = ns
Del
ta M
AP
(m
mH
g)
Iglarz M, et al. Eur Respir J 2012; 40: Suppl. 56:717s.
Dahl-Salt rat model of systemic hypertension (n = 4 to 9)Measurements in conscious animals (telemetry)Dose (by gavage): bosentan 100 mg/kg; macitentan 30 mg/kg
Pre-clinical, in vitro data and hepatic safety for macitentan
• Inhibition of BSEP, resulting in the disruption of bile salt homeostasis, is a key mechanism that may cause hepatic cholestasis and liver damage1
• Macitentan and its active metabolite do not have significant inhibitory effects on bile salt transport2,3
• In vitro studies suggest that hepatic disposition of macitentan is mainly driven by passive diffusion rather than OATP-mediated uptake4
1. Fattinger K, et al. Clin Pharmacol Ther 2001; 69:223-31.2. Raja SG. Curr Opin Investig Drugs 2010; 11:1066-73.
3. Bolli M, et al. J Med Chem 2012; 55:7849-61.4. Bruderer S, et al. AAPS 2012; 14:68-78.
Macitentan – Summary
• Macitentan is a newly developed molecule displaying:
– Optimised physicochemical properties that facilitate penetration
into the tissue
– High affinity for the ET receptors and sustained receptor binding
resulting in more effective receptor antagonism
• Pre-clinical data suggest that macitentan may have the
potential for favourable potency and efficacy
• In vitro and pre-clinical data suggests that macitentan has the
potential for favourable safety and tolerability