CRTh2: Can Residence Time Help - RSC

CRTh2: Can Residence Time Help ?

RSC-SCI Cambridge Medicinal Chemistry Symposium

Churchill College, Cambridge8-11 September 2013

Rick RobertsAlmirall

2

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”

Introduction

“Applications of Binding Kinetics to Drug Discovery”D. Swinney, Pharm. Med. (2008), 22, 23-34

In a nutshell ….

3

4

Energetic concept of Residence Time

koff=kon

Ki

Standard model

Energy

Reaction coordinate

[R] + [L]

[RL]

(R·L)‡Binding process (kon) is determined by the energy barrier Ea

Ligand concentration determines the number of attempts to get over this barrier

[R] + [L] [RL]kon

koff

Ed

Ea

G = Ed - Ea

boundunbound

Unbinding process (koff) is determined by the energy barrier Ed

Potency (Ki) is determined by the difference in these energies

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

104 10 M 1000 100 10 1 0.1 0.01

103 10 M 1000 100 10 1 0.1

102 10 M 1000 100 10 1

10 10-1 10-2 10-3 10-4 10-5 10-6 10-7 koff

Potency (nM) vs kon vs koffkon M-1 s-1

s-1

Ki, kon, koff

Very slow association

slow association

fast association

Very fast association

Very fast associating compounds that are very fast dissociating

slow associating compounds that are slow dissociatingfast associating compounds that are fast dissociating

Very slow associating compounds that are very slow dissociating

Are all equipotent

A simple binding measurement gives no clue to how fast the association and dissociation are

“inactive”

5

Reaction coordinate

[R] + [L]

[RL]

(R·L)‡

(R·L)‡

Energy

If we can control the transition state energy, we can control the binding kinetics

6

What is the transition state (R·L)‡ ?

- Molecular orbital orientation+/- etc

- 10 × from ligand - 6 × from receptor

+ interaction+ interaction+ Van der Waals interaction- Entropy of ligand+/- etc

Calculate G and hence potency

A physical process

Energy-lowering steps to get to

final bound state

Protein conformational changes

entropy

Partial electrostatic interactions

Partial desolvations

Solvated Ligand

Solvated Receptor

Molecular interaction points

Water molecules

A calculated process

Fleeting existence

7

Why bother to control Binding Kinetics ?

seconds minutes hours days

PD

PK

Residence time / Dissociation half-life

Surmountable InsurmountableMechanistic Pharmacodynamic

Functional efficacy relates to off-rate M3 agonists Mol. Pharmacol. (2009), 76, 543-551A2A agonists Br. J. Pharmacol. (2012), 166, 1846-1859

Partial agonism ↔ Full agonism

time

leve

l

Potency has little influence over these behaviours

8



PD

PK



Efficacy depends on substrate concentration

Mechanism-based toxicityDopamine D2 antagonistsClozapine as a rapidly reversible D2 antagonistHaloperidol is insurmountable and blocks basal D2 activityGI Toxicity of COX-1 inhibitors. Lett. Drug Design Disc. (2006), 3, 569Celecoxib is surmountable and free of GI ulcerationAspirin is irreversible and carries use warnings

time

leve

l

Enzyme inhibitors can cause a build-up of substrateLovastatin, an HMG-CoA reductase inhibitor is sensitive to HMG-CoA build-upCandasartan, an ACE inhibitor is insensitive to AT1 build-up

9



PD

PK



Ester hydrolysable M3 antagonistsIpratropium is dosed 2 puffs, 4 times a dayAclidinium and Tiotropium are twice and once daily respectively

time

leve

l

M3 over M2 selectivityAclidinium bromide safety profile. J. Pharm. Exp. Ther (2009), 331, 740-751

Pharmacodynamics outlasts Pharmacokinetics

Kinetic selectivity

[R] + [L] [RL]kon

koff

On rates by mechanism – also independent of potency

10

If the off rate is slow, the on rate is also slow

Reaction coordinate

[R] + [L]

[RL]

(R·L)‡

Energy

Ed

Ea

Simple fit

[R] + [L] [RL]k1

k2

[RL*]k3

k4

[RL*]

Induced fit

(RL)‡

Reaction coordinate

[R] + [L]

[RL]

(R·L)‡

Energy

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

quick

slow

Simple fit model

0

20

40

60

80

100

6 12 18 24Time (h)

% R

ecep

tor

Occ

upan

cy

On rates by mechanism

11

Simulation: Dissociation half-life 24 hConcentration of [L] at 10 × IC50

However, the time to “get on” is about 6 h.

Before this time the ligand is a partial antagonist

Once “on”, the ligand behaves as an insurmountable antagonist

Sufficient PK levels needed for sufficient time to ensure receptor becomes saturated

[R] + [L] [RL]kon

koff

If the off rate is slow, the on rate is also slow

Simple fit

[R] + [L] [RL]k1

k2

[RL*]k3

k4

Induced fit model

0

20

40

60

80

100

6 12 18 24

RL%

RL*%

Total RO%

Time (h)

% R

ecep

tor

Occ

upan

cy

Simulation: k4 Dissociation half-life 24 hConcentration of [L] at 10 × IC50

On rates by mechanism

12

Induced fit

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

Sufficient PK levels needed for sufficient time to ensure receptor becomes saturated

13

The CRTh2 Programme

14

Brief introduction to CRTh2

CRTh2 activation:

induces a reduction of intracellular cAMP and calcium mobilization.

is involved in chemotaxis of Th2 lymphocytes, eosinophils, mast cells and basophils.

inhibits the apoptosis of Th2 lymphocytes

stimulates the production of IL4, IL5, and IL13, leading to:

eosinophil recruitment and survival mucus secretion airway hyper-responsiveness immunoglobulin E (IgE) production etc

CRTh2 and DP1 review. Nat. Rev. Drug Disc. (2007), 6, 313

Real name:

Chemoattractant Receptor-homologous molecule expressed on T-Helper 2 cells

Also known as DP2

CRTh2 antagonism:

Should block pro-inflammatory PGD2 effects on key cell types

Potential benefit in: asthma allergic rhinitis atopic dermatitis.

N

OHO

S

NH

O

Cl

15

Why Long Residence Time in CRTh2 ?

IndomethacinWeak agonist

AstraZenecaAZD-1981Phase II

ActelionSetipiprantPhase III

Oxagen-EleventaOC-459

Phase III

NovartisR = CF3 QAV-039R = H QAW-680

Phase II/II

MerckMK-7246Phase I

N

OHON

SO O

F

PanmiraAM461Phase I

AstraZenecaAZD-5985 or

AZD-8075Phase I/I

BoehringerBI671800Phase II

ArrayARRY-502Phase II

AmgenAMG-853 Phase II

Pulmagen-TeijinADC-3680Phase II

RocheRG-7581Phase I

Indole acetic acids

Aryl acetic acids

Phenoxyacetic acids

OHO CF3

N

OMe

O

HN

PanmiraAM211Phase I

?

?

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)

PK Half-life vs Volume

0 6 12 18 24

AcidZwitterion

1

0.1

10

Human terminal half-life (h)

Volu

me

of d

istr

ibut

ion

(L/k

g)

Total plasma volume

Total body water volume

3.

N N

O

OH

O

N

F

H2N

H

H

F

F

OH

OOHOHHO O

H

O

DiflunisalPK t½ 10h

TrovafloxacinPK t½ 11h

PravastatinPK t½ 0.5h

ProbenecidPK t½ 5.9h

PK of carboxylic acids

16

Human PK profiles of 150 carboxylic acids

Adapted from Obach,Drug.Metab.Disp. (2008), 36, 1385

1.

2.

4.

Ideal CRTh2 zone

17

Our internal programmeWe 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


PD

PK



time

leve

l

N

HN

SO O

F

O

HO

18

Are there slow-dissociating CRTh2 antagonists?

MerckMK-7246

TM-30089(CAY-10471)

AmiraAM432

Compound Potency Dissociation half-life* Reference

Ramatroban pA2 36 nM 5 min Mol. Pharmacol. (2006), 69, 1441

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 American Thoracic Society (ATS), May 17-22, 2013

PGD2

TM-30643TM-30642Ramatroban

PulmagenADC-3680

Structure not disclosed

0

1000

2000

3000

4000

5000

100 µM1 µM10 nM0.1 nM

PGD2 Concentration

Rea

dout

19

In vitro dissociation assays CRTh2

0

200

400

600

800

1000

100 µM1 µM10 nM0.1 nM

PGD2 Concentration

Rea

dout

Readout1 h

TM-30089(CAY-10471)

GTPS binding

Membranes over-expressing human CRTh2PGD2 agonism produces allows [35S]-GTPS binding, detected by radioactivity

Ramatroban

Compound

3 h

PDG2

Readout time

ClassicalInsurmountable

inhibition

CAY-10471 0 → 5 µM

Ramatroban 0 → 10 µM

Readout15 min

Classical Surmountable

inhibition

0

1000

2000

3000

4000

5000

100 µM1 µM10 nM0.1 nM

PGD2 Concentration

Rea

dout

20


2000

4000

6000

100 µM1 µM10 nM0.1 nM

PGD2 ConcentrationR

eado

ut

Readout1 h

TM-30089(CAY-10471)

Ramatroban

Compound

3 h

PDG2

24 h

Re-mountable inhibition

Readout15 min

Readout24 h

Readout time

Surmountability is just a question of time

0

200

400

600

800

1000

100 µM1 µM10 nM0.1 nM

PGD2 Concentration

Rea

dout

Surmountability vs Insurmountability

Membranes over-expressing human CRTh2PGD2 agonism produces allows [35S]GTPS binding, detected by radioactivity

Classical Surmountable

inhibition

CAY-10471 0 → 5 µM

Ramatroban 0 → 10 µM

21


“Worst case” scenario for dissociation half-life

No rebinding possible.

Physiological system may be less demanding

Compound(5 × Ki)

2 h

PDG2(1000 × Ki)

Readout times

Washout experiments

Membranes pre-incubated with compoundAntagonist effectively swamped by agonistDecay of inhibition followed by timeFiltration reading in automated 96-well formatReadings from 2 min to 28 h

TM-30089(CAY-10471)

Ramatroban

0 4 8 12 16 20 24 28

0

20

40

60

80

100

Time (h)

Mea

n In

hibi

tion

%

0 4 8 12 16 20 24 28

0

20

40

60

80

100

Time (h)

Mea

n In

hibi

tion

%

Dissociation t1/2 < 1 min

Dissociation t1/2 ~ 80 min

Surmountable(Competitive)

Insurmountable(Non-Competitive)

22

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

Core SAR

Core Pyrazole Reverse

GTPS IC50 (nM) 7 35

Dissociation t½ (h) 0.1 0.1

N

NO

N

NH

O

** ** ** ** ** **

**

NN **

Indole Pyrrolopiperidinones (Pipas)Pyrazoles

All compounds of similar potencyCore structure has a greater effect on Residence Time

5-F-Indole

14

1.3

PiPa N-Me Pipa N-Bn Pipa diMe-Pipa

5 5 1 4

2.3 5.3 6.6 10

23

Pipa tail SAR

R1 R2 GTPS 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

Substituent changes in the tail did not greatly affect the potency

There is however an additive effect on residence time

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 1hDissociation half-life 1h

0 10 20 300

20

40

60

80

100Total RO%PK RO%

Time (h)

% R

ecep

tor

Occ

upan

cy


0 10 20 300

20

40

60

80

100Total RO%PK RO%

Time (h)

% R

ecep

tor

Occ

upan

cy


0 10 20 300

20

40

60

80

100

Total RO%PK RO%

Time (h)

% R

ecep

tor

Occ

upan

cy


0 10 20 300

20

40

60

80

100

Total RO%PK RO%

Time (h)

% R

ecep

tor

Occ

upan

cy

PK-PD Disconnection Simulations

24

At t = 0, [Ligand] = 10 × IC50

GPCR threshold

GPCR threshold

Barely observable

Barely observable

Not observable

Observable

For a recent article, see Drug Disc. Today (2013), 18, 697

3 (diMe)-Pipa 10 h 20 h

2 F-Indole 1.4 h 1 h

Human v Gp dissociation

10 20 30

10

20

30

Guinea Pig half-life (h)

Hum

an h

alf-l

ife (

h)

25

PK-PD disconnection model proof of principle

Compound

1 - 24hDK-PDG2

Readout time

1h

Accompanying PK analyses

Guinea Pig Eosinophilia assay

Guinea pigs are pre-dosed with test compoundWait 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 extractedSimultaneous eosinophil counting and PK analysis

Finding the right tool compounds

Compound Core human Guinea pig

1 (MeO,F)-Pipa 23 h 2 h

(MeO,F)-Pipa (diMe)-PipaF-indole1.

2.

3.

Species Dissociation half-lives

Indole gp PK 0.3 mg/kg p.o.

6 12 18 240.1

1

10

100

1000

10000

Time (h)

Plas

ma

conc

(ng/

ml)

26

PK-PD disconnection model

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

F-Indole guinea pig profile2h Eosinophilia IC50 40 ng/mlDissociation t½ 1.3 hPK t½ 5.3 h

Indole Eosiniophilia PK-PD

10 100 1000 10000 100000

-50

0

50

100

150

1 h

24 h

Plasma conc (ng/ml)

% In

hibi

tion

Eosi

noph

ilia

30

Dose mg/kg

30.3

0.3

3

0.03

Inhibition of eosinophilia (PD) is purely dependant upon systemic levels (PK)

No PK-PD disconnection

Pre-administration time


0 10 20 300

20

40

60

80

100

Total RO%PK RO%

Time (h)

% R

ecep

tor

Occ

upan

cy

Guinea pig 2h eosinophilia IC50

Pipa Eosinophilia

0.1 1 10 100 1000-20

0

20

40

60

80

100

120

1 h15 h

plasma conc ng/ml

% in

hibi

tion

eosi

noph

ilia

27

PK-PD disconnection model Pipa gp PK 3 mg/kg s.c.

6 12 18 240.1

1

10

100

1000

10000

Time (h)

Plas

ma

conc

(ng/

ml)

NH

N

OHO

SOO

O

diMe-Pipa guinea pig profile2h Eosinophilia IC50 7 ng/mlDissociation t½ 20 hPK t½ 0.9 h

3

0.30.3

0.03

0.003

Inhibition of eosinophilia (PD) outlasts drop in systemic levels (PK) at 17h after dosing

PK-PD disconnection (hysteresis)

Dose mg/kg

3

Guinea pig 2h eosinophilia IC50

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

Pre-administration time


0 10 20 300

20

40

60

80

100Total RO%PK RO%

Time (h)

% R

ecep

tor

Occ

upan

cy

28

How long is long residence ?

Total receptor population

1st half-life 2nd half-life 3rd half-life

Ligand lostToo dilute to rebindCleared from circulation

Saturate Receptor, then washout

Receptor Occupancy by exponential decay

0 2 4 6 8 100

20

40

60

80

100

1 3Half-lives of dissociation

Rec

epto

r O

ccup

ancy Receptor Occupancy required for a GPCR

antagonist.Pharmacol. Therap. (2009), 122, 281-301

This translates to abouthalf a Dissociation Half-life

To turn a twice-daily compoundinto a once-daily compound,we want a Dissociation Half-life of ≥ 24h

29

Where is long Residence?

Intuitive, but not that helpful. We want the most potent compounds anyway

Are more active compounds longer resident ?

Energy

Reaction coordinate

(R·L)‡Dissociation Half-life vs Potency

0.1

1

10

100

1000

Biaryl

OtherPyrazolePiPa

Std

32168421Short Residence

Dissociation Half-life (h)

GTP

S IC

50 P

oten

cy (

nM)

[R] + [L]

[RL]

[RL]

More potent

Longer resident?

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, 449Review of molecular determinants. Drug Disc. Today. (2013), 18, 667

“Non” resident 10 – 1000 nM

Long residence 1 – 100 nM

Dissociation Half-life vs TPSA

0

50

100

150BiarylPyrazolePipa6 MemCompetitorOther

Short Residence 1 2 4 8 16 32


TPSA

(Å

2 )

30

Where is long Residence?Are more Polar compounds longer resident?

Reaction coordinate

[R] + [L]

[RL]

(R·L)‡

Energy

Is desolvation relevant here?(R·L)‡

Freedom to adapt polar surface area to modulate physicochemical properties

ResTime vs Permeability

0.031250.06250.1250.25 0.5 1 2 4 8 16 320.0001

0.001

0.01

0.1

1

10

100

BiarylMonoOtherPyrRevPyrPiPaStd


PAM

PAPe

rmea

bilit

y (x

10-6

cm

/s)

Are Impermeable compounds are Long Resident in CRTh2 ?


31

Not Intuitive

ResTime vs Permeability

0.031250.06250.1250.25 0.5 1 2 4 8 16 320.0001

0.001

0.01

0.1

1

10

100

BiarylMonoOtherPyrRevPyrPiPaStd


PAM

PAPe

rmea

bilit

y (x

10-6

cm

/s)

32

Not IntuitiveAnd ultimately not true

Where is long Residence?Are Impermeable compounds are Long Resident in CRTh2 ?

Design permeable compounds for oral delivery

33


Maybe a slight overall trend ?

Are more lipophilic compounds longer resident?

Reaction coordinate

[R] + [L]

[RL]

(R·L)‡

Energy

Probably just pushes up energy of [L] in free water

[R] + [L]

More potent

Dissociation Half-life vs cLogP

0

2

4

6


BiarylPyrazolePipa6 MemCompetitorOther


cLog

P

Lipophilic molecules are often more potent,because once bound, the molecule doesn’t want to go back into the surrounding water

Dissociation Half-life vs cLogP

0

2

4

6



cLog

P

34

Where is long Residence?Are more lipophilic compounds longer resident?

OHO

NOR

R

R

5-fold increase in Dissociation half-lifeFor a 1,000,000-fold increase in lipophilicity

OHO

N

N

NO

HN

O

N

Workable in final optimisation, but not without its associated risks for oral delivery

CF3-Indole IC5037 nMDiss t½27 hcLogP5.9

7-Azaindole IC5021 nMDiss t½5 hcLogP-0.6

Within particular sub-series, there was often a relationship

isoxazoles

35

Where is long Residence?Series by series

Biaryl Series

1 min 1 2 4 8 16 32 0

20

40

60


Num

ber

of C

ompo

unds

Pyrazole Series

1 min 1 2 4 8 16 32 0

5

10

15


Num

ber o

f C

ompo

unds

Pipa Series

1 min 1 2 4 8 16 32 0

2

4

6

8

10


Num

ber

of C

ompo

unds

Other compounds

1 min 1 2 4 8 16 32 0

2

4

6

8

10


Num

ber

of C

ompo

unds

Competitor Compounds

1 min 1 2 4 8 16 32 0

1

2

3

4

5


Num

ber o

f C

ompo

unds

6-Mem Series

1 min 1 2 4 8 16 32 0

1

2

3

4

5


Num

ber o

f C

ompo

unds

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.

First example of series

N

NH

O

HO O

Ar

OHO

N

S

N

CF3

OHO

N

S

N

HN

O

36

Homing in on Residence Time in the Biaryl series

IC50 5 nM

Dissociation half-life

9 h

IC50 8 nM

inactive

IC50 4 nM

Dissociation half-life

11 h

Dissociation half-life25 min

Long Residence Time in the Biaryls comes from an H-Bond Acceptor in ortho

37

Amide Rotamers

Long Residence Time in the Biaryls comes from an H-Bond Acceptor in orthoin a specific position

IC50 14 nM Dissociation half-life 2 h

inactive

OHO CF3

N

OMe

O

IC50 27 nM half-life 1.5 h

50:50by NMR

cis trans

38

Can we check the H-Bond Acceptor location?

N

N

OHO

NO

R

N

OHONO

F

Compound 1 2

GTPS IC50 (nM) 20 6

Dissociation t½ (h) 10 18

R= Me. Ab initio calculations conformational preference

1 R = H 2

39

Can we achieve truly long residence?Position-by-position analysis of good structural features for Residence Time

Acetic acid

Benzyl to bump up lipophilicity

Chloro is OK here

Isoxazole as H-bond acceptor

7-Azaindole forphys-chem properties

methyl stub

Compound Azaindole

GTPS IC50 (nM) 2.5 nM

Dissociation t½ (h)

cLogP 4.8

cLogD 2.4

46 ± 15 h

40

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

CRTh2: Can Residence Time Help ?

Efficacy

PotencyResidenceTime

41

AcknowledgementsMedicinal ChemistryJuan Antonio AlonsoMª Antonia BuilOscar CasadoMarcos CastilloJordi CastroPaul EastwoodCristina EsteveManel FerrerPilar FornsElena GómezJacob GonzálezGalChimiaSara LópezMarta MirImma MorenoSara SevillaBernat VidalLaura VidalPere Vilaseca

Biological Reagents and ScreeningFani AlcarazMiriam AndrésJulia DíazTeresa DomènechVicente GarcíaRosa LópezAdela OrellanaSílvia PetitIsrael RamosEnric Villanova

ADMEManel de LucaPeter EichhornLaura EstrellaDolores MarinJuan NavarroMontse VivesMiriam Zanuy

Integrative PharmacologyClara ArmengolLaia BenaventLuis BoixElena CalamaAmadeu GavaldàBeatríz LergaSonia Sánchez

ManagementPaul BeswickJordi GràciaVictor MatassaMonste Miralpeix

Computational and Structural Chemistry and BiologySandra AlmerYolanda CarranzaSònia EspinosaEstrella Lozoya

Respiratory Therapeutic AreaMónica BravoMarta CalbetJosé Luís GómezEncarna JiménezMartin LehnerIsabel Pagan

DevelopmentCesc CarreraNieves CrespoJuan Pérez AndrésJuan Pérez GarcíaGemma RoglanFrancisco SánchezCarme Serra

Pathology and ToxicologyAna AndréaMariona AulíCloti HernándezNeus Prats

Intellectual PropertyHouda MelianaEulàlia Pinyol

CRTh2: Can Residence Time Help - RSC

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