CRTh2: Can Residence Time Help ?
RSC-SCI Cambridge Medicinal Chemistry Symposium
Churchill College, Cambridge
8-11 September 2013
Rick Roberts
Almirall
Introduction
Paul Ehrlich, The Lancet (1913), 182, 445
“A substance will not work unless it is bound”
100 years on:
“What a substance does may depend on
how long it is bound”
2
In a nutshell ….
Introduction
“Applications of Binding Kinetics to Drug Discovery”
D. Swinney, Pharm. Med. (2008), 22, 23-34
3
Energetic concept of Residence Time
kon
[R] + [L]
Standard model
unbound
[RL]
koff
bound
Energy
Binding process (kon) is
determined by the energy
barrier Ea
Ligand concentration
determines the number of
attempts to get over this
barrier
(R·L)‡
Ea
Ed
[R] + [L]
G = Ed - Ea
[RL]
Reaction coordinate
Potency (Ki) is determined by
the difference in these energies
Ki =
4
koff
kon
Unbinding process (koff) is
determined by the energy
barrier Ed
Ki, kon, koff
kon M
Very fast association
fast association
slow association
-1
Potency (nM) vs kon vs koff
s-1
108
10
1
0.1
0.01
0.001
107
100
10
1
0.1
0.01
0.001
106
1000
100
10
1
0.1
0.01
0.001
105
10 M
1000
100
10
1
0.1
0.01
0.001
10 M
1000
100
10
1
0.1
0.01
10 M
1000
100
10
1
0.1
10 M
1000
100
10
1
10-3
10-4
10-5
10-6
10-7
104
Very slow association
103
102
“inactive”
10
Energy
10-1
10-2
s-1
A simple binding measurement gives no clue to
how fast the association and dissociation are
(R·L)‡
Very slow associating compounds that are very slow dissociating
(R·L)‡
slow associating compounds that are slow dissociating
fast associating compounds that are fast dissociating
Very fast associating compounds that are very fast dissociating
[R] + [L]
[RL]
Reaction coordinate
5
koff
If we can control the transition state energy,
we can control the binding kinetics
Are all
equipotent
What is the transition state (R·L)‡ ?
entropy
Partial
desolvations
Protein conformational
changes
Energy-lowering
steps to get to
final bound state
Fleeting
existence
A physical process
Partial
electrostatic
interactions
Solvated
Ligand
Calculate G and
hence potency
Solvated
Receptor
A calculated process
Water molecules
Molecular interaction points
6
- 10 ×
from ligand
-6×
from receptor
- Molecular orbital orientation
+/- etc
+
interaction
+
interaction
+ Van der Waals interaction
- Entropy of ligand
+/- etc
Why bother to control Binding Kinetics ?
Residence time / Dissociation half-life
minutes
hours
days
level
seconds
PD
PK
time
Mechanistic
Surmountable
Insurmountable
Pharmacodynamic
Potency has little influence over these behaviours
Partial agonism ↔ Full agonism
Functional efficacy relates to off-rate
M3 agonists Mol. Pharmacol. (2009), 76, 543-551
A2A agonists Br. J. Pharmacol. (2012), 166, 1846-1859
7
Why bother to control Binding Kinetics ?
Residence time / Dissociation half-life
minutes
hours
days
level
seconds
PD
PK
time
Mechanistic
Surmountable
Insurmountable
Pharmacodynamic
Efficacy depends on substrate concentration
Enzyme inhibitors can cause a build-up of substrate
Lovastatin, an HMG-CoA reductase inhibitor is sensitive to HMGCoA build-up
Candasartan, an ACE inhibitor is insensitive to AT1 build-up
Mechanism-based toxicity
Dopamine D2 antagonists
Clozapine as a rapidly reversible D2 antagonist
Haloperidol is insurmountable and blocks basal D2 activity
GI Toxicity of COX-1 inhibitors. Lett. Drug Design Disc. (2006), 3, 569
Celecoxib is surmountable and free of GI ulceration
Aspirin is irreversible and carries use warnings
8
Why bother to control Binding Kinetics ?
Residence time / Dissociation half-life
minutes
hours
days
level
seconds
PD
PK
time
Mechanistic
Surmountable
Insurmountable
Pharmacodynamic
Pharmacodynamics outlasts Pharmacokinetics
Ester hydrolysable M3 antagonists
Ipratropium is dosed 2 puffs, 4 times a day
Aclidinium and Tiotropium are twice and once daily respectively
Kinetic selectivity
M3 over M2 selectivity
Aclidinium bromide safety profile. J. Pharm. Exp. Ther (2009), 331, 740-751
9
On rates by mechanism – also independent of potency
Induced fit
Simple fit
k1
kon
[R] + [L]
[RL]
[R] + [L]
[RL]
k2
koff

k3
If the off rate is slow,
the on rate is also slow
Energy



k4
The first on and off rates are quicker
Some kind of internal change takes place once bound
The final off rate is macroscopically the slowest
Energy
(RL)‡
(R·L)‡
(R·L)‡
Ea
slow
Ed
[R] + [L]
quick
[R] + [L]
[RL]
[RL]
Reaction coordinate
10
[RL*]
[RL*]
Reaction coordinate
On rates by mechanism
Simple fit
kon
[R] + [L]
[RL]
koff

If the off rate is slow,
the on rate is also slow
Once “on”, the ligand
behaves as an
insurmountable antagonist
However, the time to
“get on” is about 6 h.
Before this time the
ligand is a partial
antagonist
% Receptor Occupancy
Simple fit model
100
80
60
40
20
0
6
12
18
24
Time (h)
Simulation: Dissociation half-life 24 h
Concentration of [L] at 10 × IC50
Sufficient PK levels needed for sufficient time to ensure receptor becomes saturated
11
On rates by mechanism
Induced fit
k1
[R] + [L]
k3
[RL]
[RL*]
k2
k4
% Receptor Occupancy
The ligand binds quickly (Total RO%)
However at this point it behaves as a
classical surmountable ligand
Once “on”, the ligand
behaves as an
insurmountable antagonist
Induced fit model
100
80
Total RO%
60
RL*%
40
RL%
20
0
6
12
18
24
Time (h)
Simulation: k4 Dissociation half-life 24 h
Concentration of [L] at 10 × IC50
Sufficient PK levels needed for sufficient time to ensure receptor becomes saturated
12
The CRTh2 Programme
13
Brief introduction to CRTh2
Real name:
Chemoattractant Receptorhomologous molecule expressed
on T-Helper 2 cells
Also known as DP2
CRTh2 activation:
induces a reduction of intracellular cAMP
and calcium mobilization.
is involved in chemotaxis of Th2
lymphocytes, eosinophils, mast cells and
basophils.
CRTh2 and DP1 review. Nat. Rev. Drug Disc. (2007), 6, 313
inhibits the apoptosis of Th2 lymphocytes
CRTh2 antagonism:
stimulates the production of IL4, IL5, and
IL13, leading to:
 eosinophil recruitment and survival
 mucus secretion
 airway hyper-responsiveness
 immunoglobulin E (IgE) production
 etc
Should block pro-inflammatory PGD2 effects on
key cell types
14
Potential benefit in:
 asthma
 allergic rhinitis
 atopic dermatitis.
Why Long Residence Time in CRTh2 ?
Indole acetic acids
Cl
HO
O
HO
O
N
N
S
N
F
S
O O
?
NH
O
Oxagen-Eleventa
OC-459
Phase III
AstraZeneca
AZD-1981
Phase II
Actelion
Setipiprant
Phase III
Novartis
R = CF3 QAV-039
R = H QAW-680
Phase II/II
Merck
MK-7246
Phase I
Pulmagen-Teijin
ADC-3680
Phase II
Aryl acetic acids
?
Indomethacin
Weak agonist
Phenoxyacetic acids
Boehringer
BI671800
Phase II
Array
ARRY-502
Phase II
HN
N
HO
O
O
CF3
OMe
AstraZeneca
AZD-5985 or
AZD-8075
Phase I/I
15
Panmira
AM461
Phase I
Panmira
AM211
Phase I
Amgen
AMG-853
Phase II
Roche
RG-7581
Phase I
Volume of distribution (L/kg)
PK of carboxylic acids
Acid
Zwitterion
Human PK profiles of
150 carboxylic acids
Adapted from Obach,
Drug.Metab.Disp.
(2008), 36, 1385
PK Half-life vs Volume
10
Ideal
CRTh2
zone
2.
3.
1
Total body water volume
0.1
Total plasma volume
4.
0
6
1.
12
18
24
Human terminal half-life (h)
Techniques used to avoid rapid clearance:
1.Very high plasma protein binding (e.g. Diflunisal >99%)
2.Zwitterionic tissue distribution (e.g. Trovafloxacin, Vss 1.3 L/kg)
3.Organ distribution (e.g. Pravastatin, t½ 0.5 h, but concentrated in the liver)
4.Be small, be ignored by the liver (e.g. Probenecid, 80-90% renal excretion)
O
O
F
H
N
N
HO
N
F
H2N
Diflunisal
PK t½ 10h
16
O
OH
O
H
OH OH O
OH
H
Trovafloxacin
PK t½ 11h
F
Pravastatin
PK t½ 0.5h
Probenecid
PK t½ 5.9h
Our internal programme
We want to find a once a day, oral, low dose (≤ 10 mg) CRTh2 antagonist for mild-moderate asthma

All antagonists are acids.

Acids generally have poor PK

Clinical dosing of first CRTh2 antagonists – high dose and twice daily

Therefore, we chose to deliberately look for slowly dissociating CRTH2 antagonists:



to maintain receptor occupancy beyond normal PK and extend duration of action
to reduce the pressure of finding a carboxylic acid with desirable PK properties
to add the possibility of extra protection due to insurmountability against PGD2 burst release
hours
days
level
Residence time / Dissociation half-life
seconds
minutes
PD
PK
time
Mechanistic
17
Surmountable
Insurmountable
Pharmacodynamic
Are there slow-dissociating CRTh2 antagonists?
O
H
N
HO
F
S
O O
N
Ramatroban
TM-30642
TM-30643
TM-30089
(CAY-10471)
Structure not
disclosed
Merck
MK-7246
Compound
PGD2
Potency
Dissociation
half-life*
Amira
AM432
Pulmagen
ADC-3680
Reference
Ramatroban
pA2
36 nM
5 min
TM-30642
pA2
20 nM
8 min
--- / / ---
TM-30643
pA2
4 nM
(12.8 years)
--- / / ---
TM-30089
pA2
(13.5 years)
--- / / ---
MK-7246
Ki
2.5 nM
33 min
Mol. Pharmacol. (2011), 79, 69
PGD2
KD
11 nM
11 min
Bioorg. Med. Chem. Lett. (2011), 21, 1036
AM432
IC50
6 nM
89 min
ADC-3680
Ki
1.6 nM
20 min
18
Mol. Pharmacol. (2006), 69, 1441
--- / / --American Thoracic Society (ATS), May 17-22, 2013
In vitro dissociation assays CRTh2
GTPS binding
Compound
Membranes over-expressing human CRTh2
PGD2 agonism produces allows [35S]-GTPS
binding, detected by radioactivity
PDG2
3h
Readout time
Ramatroban 0 → 10 µM
5000
Readout
4000
Ramatroban
Readout
1h
Classical
Surmountable
inhibition
3000
2000
1000
0
0.1 nM
10 nM
1 µM
100 µM
PGD2 Concentration
1000
Readout
800
TM-30089
(CAY-10471)
600
Readout
15 min
Classical
Insurmountable
inhibition
400
200
0
0.1 nM
10 nM
1 µM
100 µM
PGD2 Concentration
CAY-10471 0 → 5 µM
19
In vitro dissociation assays CRTh2
Surmountability vs Insurmountability
Compound
Membranes over-expressing human CRTh2
PGD2 agonism produces allows [35S]GTPS
binding, detected by radioactivity
PDG2
3h
Readout time 24 h
Ramatroban 0 → 10 µM
5000
Readout
4000
Ramatroban
Readout
1h
Classical
Surmountable
inhibition
3000
2000
1000
0
0.1 nM
10 nM
1 µM
100 µM
PGD2 Concentration
Re-mountable inhibition
1000
TM-30089
(CAY-10471)
600
6000
Readout
15 min
Readout
Readout
800
400
2000
0.1 nM
20
4000
200
0
Surmountability is just a
question of time
Readout
24 h
10 nM
1 µM
100 µM
PGD2 Concentration
CAY-10471 0 → 5 µM
0.1 nM
10 nM
1 µM
PGD2 Concentration
100 µM
In vitro dissociation assays CRTh2
Washout experiments
Compound PDG2
(1000 × Ki)
(5 × Ki)
Membranes pre-incubated with compound
Antagonist effectively swamped by agonist
Decay of inhibition followed by time
Filtration reading in automated 96-well format
Readings from 2 min to 28 h
2h
Readout times
Ramatroban
Mean Inhibition %
100
Surmountable
(Competitive)
80
Dissociation t1/2 < 1 min
60
40
“Worst case” scenario for
dissociation half-life
20
0
0
4
8
21
Mean Inhibition %
20
24
28
80
Dissociation t1/2 ~ 80 min
60
40
20
0
0
Insurmountable
(Non-Competitive)
16
Time (h)
100
TM-30089
(CAY-10471)
12
4
8
12
16
Time (h)
20
24
28
No rebinding possible.
Physiological system may
be less demanding
Pyrazoles and Pipas
 First series of Pyrazoles gave active compounds, but no residence
 Indole nucleus developed by Oxagen. Beginnings of slow dissociation observed
 Pyrrolopiperidinones (Pipas) gave both activity and the first observations of long residence
* *
Pyrazoles
*
Core SAR
N*
N
*
Indole
*
*
*
Pyrrolopiperidinones (Pipas)
*
*
*
*
*N
*
N
O
*N
*
N
H
O
Core
Pyrazole
Reverse
5-F-Indole
PiPa
N-Me Pipa
N-Bn Pipa
diMe-Pipa
GTPS IC50 (nM)
7
35
14
5
5
1
4
Dissociation t½ (h)
0.1
0.1
1.3
2.3
5.3
6.6
10
All compounds of similar potency
Core structure has a greater effect on Residence Time
22
Pipa tail SAR
 Substituent changes in the tail did not greatly affect the potency
 There is however an additive effect on residence time
23
R1
R2
GTPS IC50
Dissociation t½
H
H
5 nM
2.3 h
MeO
H
4 nM
4.2 h
H
F
5 nM
3.3 h
MeO
F
7 nM
23 h

Pipa series was essentially impermeable.

Not suitable for an oral program

Still, a valuable tool to validate the PK-PD disconnection in guinea pig
PK half-life 1h
Dissociation half-life 1h
PK half-life 1h
Dissociation half-life 12h
100
100
Total RO%
PK RO%
80
% Receptor Occupancy
% Receptor Occupancy
PK-PD Disconnection Simulations
60
Barely
observable
40
20
Total RO%
PK RO%
80
40
Observable
20
0
0
10
20
30
0
10
Time (h)
20
PK half-life 12h
Dissociation half-life 1h
PK half-life 12h
Dissociation half-life 12h
100
100
80
Not observable
60
40
Total RO%
PK RO%
20
30
Time (h)
% Receptor Occupancy
% Receptor Occupancy
GPCR
threshold
60
0
0
80
GPCR
threshold
Barely
observable
60
40
Total RO%
PK RO%
20
0
0
10
20
30
Time (h)
For a recent article, see Drug Disc. Today (2013), 18, 697
24
At t = 0, [Ligand] = 10 × IC50
0
10
20
Time (h)
30
PK-PD disconnection model proof of principle
Guinea Pig Eosinophilia assay
Compound
Guinea pigs are pre-dosed with test compound
Wait desired time: 1h, 5h, 17h, 24h …..
Anaesthetised animals dosed with i.v. DK-PGD2,
DK-PGD2 via CRTh2 causes liberation of
eosinophils from bone marrow to plasma
After 1 h blood is extracted
Simultaneous eosinophil counting and PK analysis
DK-PDG2
1 - 24h
1h
Readout time
Accompanying PK analyses
Finding the right tool compounds
Human v Gp dissociation
Human half-life (h)
30
(MeO,F)-Pipa
1.
(diMe)-Pipa
Species Dissociation half-lives
20
Compound
Core
human
Guinea pig
1
(MeO,F)-Pipa
23 h
2h
2
F-Indole
1.4 h
1h
3
(diMe)-Pipa
10 h
20 h
3.
10
2.
10
20
Guinea Pig half-life (h)
25
F-indole
30
PK-PD disconnection model
Indole gp PK 0.3 mg/kg p.o.
Plasma conc (ng/ml)
10000
F-Indole guinea pig profile
2h Eosinophilia IC50
40 ng/ml
Dissociation t½
1.3 h
PK t½
5.3 h
Guinea pig 2h
eosinophilia IC50
1000
100
10
1
6
12
18
24
Time (h)
0.1
Series
Dose
Cmax (ng/ml)
AUCinf (ng/ml/h)
Cl/F (ml/min/kg)
Vz/F (L/kg)
t1/2 (h)
Indole
0.3 mg/kg p.o.
481
4796
1
0.47
5.3
1h
 No PK-PD disconnection
24 h
% Receptor Occupancy
PK half-life 12h
Dissociation half-life 1h
100
80
60
40
Total RO%
PK RO%
20
0
0
10
20
Time (h)
26
Pre-administration
time
150
30
% Inhibition Eosinophilia
 Inhibition of eosinophilia (PD) is
purely dependant upon systemic
levels (PK)
Indole Eosiniophilia PK-PD
30
3
100
3
0.3
50
0.3
Dose mg/kg
0
0.03
-50
10
100
1000
10000
Plasma conc (ng/ml)
100000
PK-PD disconnection model
O
10000
N
Plasma conc (ng/ml)
HO
Pipa gp PK 3 mg/kg s.c.
S
O
O
O
N
H
diMe-Pipa guinea pig profile
2h Eosinophilia IC50
7 ng/ml
Dissociation t½
20 h
PK t½
0.9 h
Guinea pig 2h
eosinophilia IC50
1000
100
10
1
6
12
18
24
Time (h)
0.1
Series
Dose
Cmax (ng/ml)
AUCinf (ng/ml/h)
Cl/F (ml/min/kg)
Vz/F (L/kg)
t1/2 (h)
Pipa
3 mg/kg s.c.
1633
2619
20
1.5
0.9
 Inhibition of eosinophilia (PD)
outlasts drop in systemic levels
(PK) at 17h after dosing
Pre-administration
time
120
100
Total RO%
PK RO%
80
80
3
0.3
0.3
60
0.03
40
Dose mg/kg
20
60
0
40
-20
0.003
0.1
1
10
plasma conc ng/ml
20
0
0
10
20
Time (h)
27
% inhibition
eosinophilia
% Receptor Occupancy
PK half-life 1h
Dissociation half-life 12h
15 h
3
100
1h
 PK-PD disconnection (hysteresis)
Pipa Eosinophilia
30
100
1000
How long is long residence ?
Saturate Receptor,
then washout
1st half-life
2nd half-life
3rd half-life
Total receptor
population
Ligand lost
Too dilute to rebind
Cleared from circulation
Receptor Occupancy by exponential decay
Receptor Occupancy
100
Receptor Occupancy required for a GPCR
antagonist.
Pharmacol. Therap. (2009), 122, 281-301
80
60
This translates to about
half a Dissociation Half-life
40
20
0
0
1
2
3
4
6
8
Half-lives of dissociation
28
10
To turn a twice-daily compound
into a once-daily compound,
we want a Dissociation Half-life of ≥ 24h
Where is long Residence?
Selected lit reports or Structure Residence Relationships (SRRs)
Trend analysis of D2 antagonists. Bioorg. Med. Chem (2011), 19, 2231.
Trend analysis of Pfizer and literature data. Med. Chem. Comm. (2012), 3, 449
Review of molecular determinants. Drug Disc. Today. (2013), 18, 667
Are more active compounds longer resident ?
Dissociation Half-life vs Potency
(R·L)‡
[R] + [L]
More
potent
Longer
resident?
[RL]
GTP S IC50 Potency (nM)
Energy
Long residence
1 – 100 nM
1000
Biaryl
100
PiPa
Pyrazole
Other
10
1
0.1
Short Residence
[RL]
Std
“Non” resident
10 – 1000 nM
1
2
4
Dissociation Half-life (h)
Reaction coordinate
Intuitive, but not that helpful. We want the most potent compounds anyway
29
8
16 32
Where is long Residence?
Are more Polar compounds longer resident?
(R·L)‡
Energy
Is desolvation
relevant here?
Dissociation Half-life vs TPSA
(R·L)‡
TPSA (Å2 )
150
[R] + [L]
[RL]
Reaction coordinate
Biaryl
Pyrazole
Pipa
6 Mem
Competitor
Other
100
50
0
Short Residence
1
2
4
8 16 32
Dissociation Half-life (h)
Freedom to adapt polar surface area to modulate physicochemical properties
30
Where is long Residence?
Are Impermeable compounds are Long Resident in CRTh2 ?
PAMPA
Permeability (x10-6 cm/s)
ResTime vs Permeability
100
10
Biaryl
Mono
Other
Pyr
RevPyr
PiPa
Std
1
0.1
0.01
0.001
0.0001
0.03125
0.0625
0.1250.25 0.5
1
2
4
8
Dissociation Half-life (h)
Not Intuitive
31
16 32
Where is long Residence?
Are Impermeable compounds are Long Resident in CRTh2 ?
PAMPA
Permeability (x10-6 cm/s)
ResTime vs Permeability
100
10
Biaryl
Mono
Other
Pyr
RevPyr
PiPa
Std
1
0.1
0.01
0.001
0.0001
0.03125
0.0625
0.1250.25 0.5
1
2
4
8
Dissociation Half-life (h)
Not Intuitive
And ultimately not true
Design permeable compounds for oral delivery
32
16 32
Where is long Residence?
Are more lipophilic compounds longer resident?
Energy
Dissociation Half-life vs cLogP
(R·L)‡
Biaryl
Pyrazole
Pipa
6 Mem
Competitor
Other
6
cLogP
[R] + [L]
[R] + [L]
More
potent
[RL]
Reaction coordinate
Probably just pushes up
energy of [L] in free water
4
2
0
Short Residence
1
2 4
8 16 32
Dissociation Half-life (h)
Maybe a slight overall trend ?
Lipophilic molecules are often more potent,
because once bound, the molecule doesn’t want to go back into the surrounding water
33
Where is long Residence?
Are more lipophilic compounds longer resident?
Within particular sub-series, there was often a relationship
O
N
7-Azaindole
O
IC50
N
21 nM
HN
N
Diss
N
t½
5h
cLogP
-0.6
CF3-Indole
IC50
37 nM
Diss
t½
27 h
cLogP
5.9
5-fold increase in Dissociation
half-life
Dissociation Half-life vs cLogP
O
R
6
HO
O
O
N
R
R
cLogP
HO
4
isoxazoles
2
0
Short Residence
1
2
4
8 16 32
Dissociation Half-life (h)
For a 1,000,000-fold increase in lipophilicity
Workable in final optimisation, but not without its associated risks for oral delivery
34
Where is long Residence?
Series by series
First example of series
6-Mem Series
10
5
0
5
4
3
2
1
0
1 min
1
2 4
8 16 32
2
1
1
2 4
8 16 32
1 min
1
2 4
Pipa Series
Biaryl Series
Other compounds
Ar
N
H
O
2
60
Number of Compounds
O
6
40
20
0
0
1
2 4
8 16 32
Dissociation Half-life (h)
10
8
6
4
2
0
1 min
1
2 4
8 16 32
Dissociation Half-life (h)
1 min
1
2 4
8 16 32
Dissociation Half-life (h)
 Chemical series drives Residence Time: If you’ve got it, you’ve got it and if you don’t, you don’t
 First compound of series dictates the trend.
35
8 16 32
Dissociation Half-life (h)
N
1 min
3
Dissociation Half-life (h)
8
4
4
Dissociation Half-life (h)
10
HO
5
0
1 min
Number of Compounds
Number of Compounds
Competitor Compounds
Number of Compounds
15
Number of Compounds
Number of Compounds
Pyrazole Series
Homing in on Residence Time in the Biaryl series
IC50 8 nM
IC50 5 nM
Dissociation
half-life
11 h
Dissociation
half-life
9h
HO
S
O
HO
S
O
O
inactive
N
N
CF3
N
HN
N
Long Residence Time in the Biaryls comes from an H-Bond Acceptor in ortho
36
IC50 4 nM
Dissociation
half-life
25 min
Amide Rotamers
N
HO
O
O
CF3
cis
OMe
inactive
50:50
by NMR
trans
IC50 14 nM
Dissociation
half-life 2 h
IC50 27 nM
half-life 1.5 h
Long Residence Time in the Biaryls comes from an H-Bond Acceptor in ortho
in a specific position
37
Can we check the H-Bond Acceptor location?
O
HO
N
O
HO
O
R
1R=H
F
R= Me. Ab initio calculations
38
O
N
N
N
N
2
conformational preference
Compound
1
2
GTPS IC50 (nM)
20
6
Dissociation t½ (h)
10
18
Can we achieve truly long residence?
Position-by-position analysis of good
structural features for Residence Time
Benzyl to bump up lipophilicity
Isoxazole as H-bond acceptor
Acetic acid
Chloro is OK here
7-Azaindole for
phys-chem
properties
methyl stub
Compound
GTPS IC50 (nM)
Dissociation t½ (h)
39
Azaindole
2.5 nM
46 ± 15 h
cLogP
4.8
cLogD
2.4
CRTh2: Can Residence Time Help ?

For a purely antagonistic effect, prolonging Receptor Occupancy prolongs PD effect

You will only really appreciate a PK-PD disconnection if Dissociation half-life >> PK terminal half-life

For GPCR antagonism, you should count on extending the PD effect by half a half-life

A “PK phase” of antagonism is needed to “set” the ligand in the receptor, regardless of mechanism

We are pretty good at explaining what’s behind Structure-Activity Relationships (SAR)
Structure-Residence Relationships (SRR) are in their infancy and/or qualitative

To find Long Residence, you need to look for it
Efficacy
Residence
Time
40
Potency
Acknowledgements
Medicinal Chemistry
Juan Antonio Alonso
Mª Antonia Buil
Oscar Casado
Marcos Castillo
Jordi Castro
Paul Eastwood
Cristina Esteve
Manel Ferrer
Pilar Forns
Elena Gómez
Jacob González
GalChimia
Sara López
Marta Mir
Imma Moreno
Sara Sevilla
Bernat Vidal
Laura Vidal
Pere Vilaseca
ADME
Manel de Luca
Peter Eichhorn
Laura Estrella
Dolores Marin
Juan Navarro
Montse Vives
Miriam Zanuy
41
Respiratory Therapeutic Area
Mónica Bravo
Marta Calbet
José Luís Gómez
Encarna Jiménez
Martin Lehner
Isabel Pagan
Biological Reagents and Screening
Fani Alcaraz
Miriam Andrés
Julia Díaz
Teresa Domènech
Vicente García
Rosa López
Adela Orellana
Sílvia Petit
Israel Ramos
Enric Villanova
Integrative Pharmacology
Clara Armengol
Laia Benavent
Luis Boix
Elena Calama
Amadeu Gavaldà
Beatríz Lerga
Sonia Sánchez
Computational and Structural
Chemistry and Biology
Sandra Almer
Yolanda Carranza
Sònia Espinosa
Estrella Lozoya
Pathology and Toxicology
Ana Andréa
Mariona Aulí
Cloti Hernández
Neus Prats
Development
Cesc Carrera
Nieves Crespo
Juan Pérez Andrés
Juan Pérez García
Gemma Roglan
Francisco Sánchez
Carme Serra
Intellectual Property
Houda Meliana
Eulàlia Pinyol
Management
Paul Beswick
Jordi Gràcia
Victor Matassa
Monste Miralpeix