CRTh2: Can Residence Time Help ? RSC-SCI Symposium on GPCR2 in Medicinal Chemistry Allschwil, Basel 15-17 September 2014 Rick Roberts Almirall Barcelona, Spain Introduction Paul Ehrlich, The Lancet (1913), 182, 445 “A substance will not work unless it is bound” 100 years on: “What What a substance does once it’s it s bound may depend on how long it’s bound for” 2 The influence of Binding Kinetics Residence time / Dissociation half-life minutes hours days level seconds PD PK time Mechanistic Partial vs Full agonism M3 agonists A2A agonists Surmountable Efficacy vs substrate concentration Lovastatin Candasartan Mechanism-based toxicity Clozapine Haloperidol Celecoxib Aspirin Potency has little influence over these behaviours 3 Insurmountable Pharmacodynamic Duration of Action Ipratropium vs Aclidinium Kinetic Selectivity M3 vs M2 antagonism The CRTh2 Programme 4 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 i hil recruitment i and d survival i l mucus secretion airway hyper-responsiveness immunoglobulin E (IgE) production etc t Should block pro-inflammatory PGD2 effects on key cell types 5 Potential benefit in: asthma allergic rhinitis atopic dermatitis. CRTh2 – A Target of interest Indole acetic acids HO O N N ? F Oxagen-Eleventa OC-459 Phase III AstraZeneca AZD-1981 Phase II Actelion Setipiprant Phase III Novartis R = CF3 QAW-039 R = H QAV-680 Phase II/II Aryl acetic acids Merck MK-7246 Phase I Pulmagen-Teijin ADC-3680 Phase II Phenoxyacetic acids ? Boehringer BI671800 Phase II Array ARRY-502 Phase II Roche RG-7581 Phase I AstraZeneca AZD-5985 or AZD-8075 Phase I/I All compounds are acids Panmira AM461 Phase I 6 Panmira AM211 Phase I Amgen AMG-853 Phase II Plenty of Competition Plenty of Attrition First compounds high dose and/or BID Our internal programme We want to find a Once-a-day Oral low dose (≤ 10 mg) CRTh2 antagonist for mild-moderate asthma To maintain receptor occupancy beyond normal PK and extend duration of action level Therefore, we chose to deliberately look for slowly dissociating CRTh2 antagonists: PD PK to reduce the pressure of finding a carboxylic acid with desirable PK properties time Pharmacodynamic to add the possibility of extra protection due to insurmountability against PGD2 burst Insurmountable 7 Assays 8 GTPS vs PGD2 binding [3H]PG GD2 IC50 (nM) [3H]PGD2 [35S]GTPS Good correlation [35S]GTPS Assay favoured 9 [35S]GTPS IC50 (nM) CRTH2 Whole cell Isolated Eosinophiil Shape Ch hange IC50 (nM) GTPS vs ESC Isolated cell membranes Compounds show higher potency t in i cellular ll l assay + 0.1% BSA Protein binding plays a role 10 [35S]GTPS IC50 (nM) GTPS vs ESC Human Whole Blood Whole cell + 4% HSA Eosiinophil Sha ape Chang ge IC50 (nM) CRTH2 More affinity for HSA > BSA membranes More affinity for BSA > HSA + 0.1% BSA “Shift” assay y simply p y reflects affinity y of compounds for BSA and HSA. ESC IC50 is “Real” Potency 11 [35S]GTPS IC50 (nM) DP1 PGD2 Prostanoiid Recepto or DP1 %Inh hibition at 10 µM GTPS vs DP1 Receptor Selectivity >50% DP1 inhibition at 10 µM CRTh2 [35S]GTPS IC50 (nM) 12 GTPS vs TP Receptor Selectivity TP PGD2 T Thrombox xane Recep ptor TP %In nhibition att 10 µM TXA2 >50% TP inhibition at 10 µM CRTh2 Compounds are CRTh2 selective 13 [35S]GTPS IC50 (nM) In vitro dissociation assays CRTh2 GTPS binding Compound Membranes over-expressing human CRTh2 PGD2 agonism produces allows [35S]-GTPS binding, detected by radioactivity PDG2 3h R d t time Readout ti Ramatroban 0 → 10 µM 5000 Readout 4000 Ramatroban Readout 1h Classical Cl i l Surmountable inhibition 3000 2000 1000 0 0.1 nM 10 nM 1 µM 100 µM PGD2 Concentration 1000 R 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 14 In vitro dissociation assays CRTh2 Surmountability vs Insurmountability Compound Membranes over-expressing human CRTh2 PGD2 agonism produces allows [35S]GTPS binding, detected by radioactivity PDG2 3h 24 h R d t time Readout ti Ramatroban 0 → 10 µM 5000 Readout 4000 Ramatroban Readout 1h Classical Cl i l 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 R Readout R 800 400 2000 0.1 nM 15 4000 200 0 Surmountability S t bilit is i jjustt 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 When is the insurmountable surmountable ? Classical Insurmountable inhibition Competitive compounds with different kinetics Observational timescale A B timescale A Observational timescale B Classical Surmountable inhibition B seems immobile in the e periment Insurmountable experiment: Ins rmo ntable A and B reach equilibrium during the experiment. Surmountable behaviour timescale PGD2 Release from Mast cells PGD2 Kinetics ~15 min PGD2 Metabolism ~15 15 min CRTh2 antagonist Kinetics ~24 h PGD2 burst timescale Long resident CRTh2 antagonists will have an insurmountable behaviour against PGD2 burst 16 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 Automated Filtration reading g in 96-well format Readings from 2 min to 28 h 2h R d t ti Readout times Ramatroban Mean Inhibition n% 100 Surmountable 80 Dissociation t1/2 < 1 min 60 40 “Worst case” scenario for dissociation half-life f f 20 0 0 4 8 17 Mea an Inhibition % 20 24 28 80 Dissociation t1/2 ~ 80 min 60 40 20 0 0 Insurmountable 16 Time (h) 100 TM-30089 (CAY-10471) 12 4 8 12 16 Time (h) 20 24 28 No rebinding possible. Physiological Ph i l i l system t may be less demanding Mechanisms of slow dissociation 18 On rates by mechanism – also independent of potency Simple fit Induced fit k1 kon [R] + [L] [RL] [R] + [L] k3 [RL] k2 koff Energy k4 Energy ((RL))‡ (R·L)‡ (R·L)‡ Ea slow Ed [R] + [L] quick [R] + [L] [RL] [RL] Reaction coordinate 19 [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 % Recep ptor Occupan ncy 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 20 On rates by mechanism Induced fit k1 [R] + [L] k3 [RL] [RL*] k2 k4 % Recep ptor Occupan ncy 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 21 Which mechanism is it ? No radio-labelled radio labelled ligands No Biacore Slow dissociating compounds get more potent with time IC50 (nM M) Compound Dissociation half-life Compounds are active from t=0 “Real” potency may be better than in vitro potency 22 Changes in potency not sufficient to estimate which mechanism is acting Which mechanism is it ? [[R]] + [L] [ ] k3 [[RL]] k2 [[RL*]] k4 2 h Pre-incubation at 10 × IC50 Dissociation t1/2 25 h ± 3.5 % Rece eptor Occupa ancy k1 Induced fit model 100 80 Total RO% 60 RL*% 40 RL% 20 0 6 12 Time (h) Majority j y [[RL*]] fast Dissociation Residual [RL] fast Dissociation M h i Mechanism unknown, k b but iinduced d d fifit suspected d 23 18 24 How long is long? Mechanistic or Pharmacodynamic? Necessary Receptor Occupancy for efficacy - Pharmacodynamic T Target t Cl Class R Receptor t O Occupancy GPCR Antagonist 60-80% Agonist high efficacy 2-30% Agonist low efficacy 60-95% Antagonist 65-95% Agonist 5-80% Transporters All 60-85% Enzyme Inhibitors 70-99% Ligand-gated ion channels Grimwood and Hartig, Pharm. Therap. 122, 281, 2009 Expanded zone: 0 – 1 half half-life life Exponential Decay Exponential Decay 100 80 Sometime here, a GPCR antagonist will stop being effective after washout 60 40 2 3 20 4 5 0 0 2 4 6 8 10 Recepto or Occupanc cy Recepttor Occupan ncy 100 95% 90% 70% 60% 60 40 20 0 0.0 Half-lives For a GPCR antagonist, count on about half a half-life extra of PD effect 24 80% 80 0.2 0.4 0.6 Half-lives 0.8 1.0 DoA Scenarios for full coverage over 24h Many CRTh2 antagonists in the clinic are twice daily PK only effect: “classic” drug. PK-PD relationship Some PK Some residence time PK PK Cmax PD effect PK Koff Koff Cmax Residual activity at 24h Plasma levels IC50 IC50 t=0 Little PK Really long residence time Dissociation Half-life = not necessary IC50 24 h Dissociation Half-life ~ 24 h 24 h t=0 Dissociation Half-life ~ 48 h To turn a twice-daily compound into a once-daily compound, we want to add on a Dissociation half-life of ≥ 24h 25 Chemical Series Structure-Activity Relationships (SAR) St Structure-Kinetic t Ki ti Relationships R l ti hi (SKR) 26 Are there slow-dissociating CRTh2 antagonists? Ramatroban TM-30642 TM-30643 TM-30089 (CAY-10471) Structure not disclosed Merck MK-7246 C Compound d PGD2 P t Potency Dissociation half-life* Amira AM432 Pulmagen ADC-3680 R f Reference Ramatroban pA2 36 nM 5 min TM-30642 pA2 p 20 nM 8 min 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 QAW-039 Kd 1 nM 12 min ERS 8 September 2014 QAV 680 QAV-680 Kd 15 nM 1 min ERS 8 September 2014 Published residence times are all “short” 27 Mol. Pharmacol. (2006), 69, 1441 --- / / --- --- / / --- Pyrazoles Indole nucleus developed by Oxagen. Beginnings of slow dissociation observed First series of Pyrazoles gave active compounds, but no significant residence time (BMCL, 2013, 23, 3349) Second series of Reverse Pyrazoles gave a similar story (Eur J Med Chem, 2014, 71, 168) Indole Pyrazoles Reverse Pyrazoles Ph General Oxagen X = CH X=N General GTPS IC50 (nM) 14 7 4 4 – 100 35 32 – 450 Dissociation t½ (h) 1.3 0.2 1.9 0.02 – 0.7 0.2 0.04 – 0.7 SAR pretty good. No SKR advances observed in either core or tail sections Pyrazoles series abandoned for general lack of Residence time 28 Pipas Third series of Pyrazolopyrimidinones (Pipas) gave active compounds with long residence (BMCL Accepted for publication) Core SAR flat. Core SKR varied Pyrazolopyrimidinones (Pipas) * * * * * * * * * * * * Indole Oxagen PiPa N-Me N-Bn diMe N-Me* N-CHF2* GTPS IC50 (nM) 14 5 5 1 4 5 2 Dissociation t½ (h) 1.3 2.3 5.3 6.6 10 8 21 29 Pipas Tail SAR flat. Tail SKR varied Sulphone positioning ultimately affects SKR O HO O S R O N Ortho substitution N H O Para substitution R1 R2 GTPS IC50 Dissociation t½ R GTPS IC50 Dissociation t½ H H 5 nM 2.3 h Ph 170 nM n.d. MeO H 4 nM 4.2 h Me 900 nM n.d. H F 5 nM 33h 3.3 B Bn 3 nM M 09h 0.9 MeO F 7 nM 23 h 30 Pipa series was essentially impermeable. Not suitable for an oral programme. Series abandoned due to impermeability Ultimately Potent but no duration Biaryl series Fourth series of diverse biaryl compounds finally gave good activity and long residence time (BMCL Accepted for publication) Core SAR and SKR varied HO N O O CF3 A Bicyclic Heterocycle * * * * * * * * * * * * * * 5,6-ring 6,5-ring Amira Indazole Indazole Indole Indazole Indole Azaindole GTPS IC50 (nM) 16 48 48 19 19 37 9 Di Dissociation i ti t½ (h) 2 14 1.4 12 1.2 40 4.0 16 1.6 25 2.5 23 2.3 31 Biaryl series – Indazole core 6 member ring g SAR flat. SKR varied R1 R2 GTPS IC50 Dissociation t½ H H 19 nM 1.6 h Cl H 6 nM 3.2 h F H 4 nM 5h H Cl 16 nM 28h 2.8 F Cl 15 nM 10.5 h Small substituents in R1 led to moderate increased in both potency and dissociation t1/2 Substitution in R2 led to minimal changes in binding potency G d starting Good t ti point i t for f the th search h off the th desired d i d Residence R id ti time 32 Species differences Percentage of identical residues among all ungapped positions between the pairs pairs. Human Human Guinea Pig Rat Mouse 100% 73% 78% 80% 100% 69% 70% 100% 94% Guinea Pig Rat Mouse How similar are these species ? 33 100% Guinea a Pig IC50 (n nM) GTPS potencies human vs GP Similar Potencies Human IC50 (nM) 34 GTP human vs GP Residence Time species t½ Human 2h Guinea pig 29 h species t½ Human 23 h Guinea pig 1.9 h Guinea Pig Dissoc ciation halff-life (h) Mechanistically useful Pharmacologically useful Human Dissociation half-life (h) 35 PK-PD Disconnection Simulations PK half-life 1 h “PD” GPCR threshold A 1 h Dissociation half-life is barely y noticeable in the PD Poor drug – short duration of action A 12 h Dissociation half-life is definitely observable A short acting drug keeps working long beyond its expectations t ti At t = 0, [Ligand] = 10×IC50 PK half-life 12 h “PD” GPCR threshold A 1 h Dissociation half-life goes completely unnoticed Good PK means once-a-day dosing A 12 h Dissociation half half-life life is barely noticeable A great drug is really efficacious over 24 h At t = 0, [Ligand] = 10 10×IC IC50 Next day Next dose For the greatest observable effect, Dissociation half-life >> PK half-life 36 For a recent article, see Drug Disc. Today (2013), 18, 697 PK-PD disconnection model 3 mg / kg dose diMe-Pyrrolopiridinone guinea pig profile Eosinophilia IC50 3 ng/ml Dissociation t½ 20 h PK t½ 0.9 h PK Timepoint Plasma Pl levels Eosinophilia E i hili Inhibition 1h 1300 ng/ml 100% 15 h undetectable 70% %Inhibition of Eosinophilia Koff 100 Short PK, Long residence time PK-PD disconnection 80 IC50 3 ng/ml 70 % Residual activity at 15h PK 60 40 20 0 37 Koff Residual activity at 24h IC50 t=0 24 h PK-PD Disconnection in Guinea Pig Eosinophilia O Oxagen BiA l BiAryl PiP PiPas Eosinophilia IC50 (ng/ml) ~50 ~40 ~5 Gp p Dissociation Half-life 1h 15 h 20 h Gp Pharmacokinetic Half-life 5h 3h 0.9 h Oxagen PK-PD 2h 24h Good PK Short Dissociation No separation PK-PD OK PK Good Dissociation Small separation PK-PD Long g residence time translates to a PK-PD disconnection Remember: half a half-life 38 Poor PK Good Dissociation Large separation PK-PD Molecular Determinants of Long Residence 39 Where is long Residence? Selected general reports or Structure Kinetic Relationships (SKRs) 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 determinants. Drug Disc. Disc Today. Today (2013), (2013) 18, 18 667 Molecular size / weight ? Lipophilicity ? Charged state ? Rigidity ? Don’t know ? Selected specific reports or Structure Kinetic Relationships (SKRs) Therapeutic Complement Inhibitors. J. Mol. Recognit. (2009), 22, 495 Slow dissociation M3 antagonists. J. Med. Chem. (2011), 54, 6888 CCR2 antagonists. g J. Med. Chem. ((2013), ), 56,, 7706 CDK8/CycC inhibitors. PNAS (2013), 110, 8081. Adenosine A1 Receptor antagonists. J. Med. Chem. (2014), 57, 3213 40 Energetic concept of Residence Time Standard model kon [R] + [L] unbound [RL] koff bound Energy SKR Structure Kinetic Relationships (SKRs) h have b been llargely l iignored: d Residence Time Dissociation half-life Slow or fast kinetics Off-rate, koff (R·L)‡ The Dissociation rate is controlled by 2 factors: Off rate koff (1) The potency (SAR) (2) The Transition state energy [R] + [L] Potency Ki [RL] (R·L)‡ Potency P t can b be measured d If we can control the transition state energy, we can control the binding kinetics 41 Where is Long Residence ? Are more active compounds longer resident ? CDK8/CycC inhibitors PNAS (2013), 110, 8081. Energy Kd Diss t½ 5820 nM < 1.4 min Kd Diss t½ 10 nM 32 h (R·L)‡ ~1 order of magnitude of stickiness “stickiness” [R] + [L] More potent Longer resident? [RL] [RL] Reaction coordinate Clearly, Residence Time is linked to Potency 42 Where is long Residence? Are more active compounds longer resident ? (R·L)‡ OH Cl O Cl N H O O IC50 Di t½ Diss Slower On/off Energy O 8 nM 5 min i OMe IC50 Di t½ Diss 98 nM 21 h (R·L)‡ CRTh2 program data 4 orders d off magnitude it d off “stickiness” [R] + [L] More potent Longer resident? [RL] [RL] Reaction coordinate We are affecting g the transition state more than the final binding position 43 Homing in on Residence Time in the Biaryl series 4-Azaindole Me-4-Azaindole GTPS IC50 (nM) 14 16 Dissociation t½ (h) 13 1.3 21 A Magic Methyl for SKR ? 44 Homing in on Residence Time in the Biaryl series IC50 5 nM IC50 8 nM Dissociation Di i ti half-life 9h Dissociation Di i ti half-life 11 h HO S O O inactive N HN N Long Residence Time in the Biaryls comes from an H-Bond Acceptor in ortho 45 IC50 4 nM Dissociation half-life 2 min 25 i Amide Rotamers 50:50 by NMR IC50 14 nM Dissociation half-life 2 h N HO O N HO CF3 O OMe O CF3 O OMe inactive IC50 27 nM half-life half life 1.5 h Long Residence Time in the Biaryls comes from an H-Bond Acceptor in ortho in a specific position 46 H-Bond Acceptors – Steric requirements Do very subtle steric effects first determine Potency binding, then residence binding? R3 H H H H H N N N N N N R3 Sterics Potency Residence O N N N O N N Me Fused Pyrazole Isoxazole Triazole Amide Large g Low - Medium Medium Low Small High Medium Minimum High High Minimum High High High High H O H N R1 H Steric Requirements for HBA H N N H H H N N R3 ≤ H Bn R3 R1 Sterics Potency R id Residence 47 Oxazole Pyrazole Pyrazole Minimum Low - Small Medium - Large High M di Medium R1 > H R1 X R2 R2 > H Can we check the H-Bond Acceptor location? O HO S O N O N F 2 Ab initio minimisation 48 Compound 1 2 3 GTPS IC50 20 nM 4 nM 6 nM Dissociation t½ 10 h 1.7 h 18 h Can we achieve truly long residence? If we understand it, we can harness it. Position-by-position analysis of good structural features for Residence Time Minimum expression of potency and long residence Benzyl to bump up lipophilicity 3º amide as H-bond acceptor Isoxazole as H-bond acceptor Acetic acid O HO N O N Chloro is OK here Cl N methyl stub Azaindole Azaindole GTPS IC50 (nM) 14 nM GTPS IC50 (nM) Dissociation t½ (h) 1.5 h Dissociation t½ (h) 2.5 nM 46 ± 15 h cLogP 1.1 cLogP 4.8 cLogD -1.1 cLogD 2.4 Once-a-day purely from Residence Time ? 49 Lead Compound Profile In vitro and In vivo Physical Chemistry human GTPS IC50 4 nM Solubility pH 1 and 7.4 ESC hWB IC50 3 nM LogD Dissociation t½ (h) 22 h Caco (AB/BA) gp GTPS IC50 (nM) 3 nM Dissociation t½ (h) 14 h Eosinophilia IC50 4 nM Eosinophilia ID50 at 2 h PK-PD Disconnection 0.020 mg/kg Yes hERG, Nav1.5, Cav1.2 Working heart Cytotox > 10 µM Clean > 100 µM 1.3 24 / 6 Pharmacokinetics Rat Clearance Volume 9 ml/min/kg 0.5 L/kg Terminal half-life 1.6 h Bioavailability 80% Dog Clearance Safety > 1 mg/ml Volume Terminal half-life Bioavailability 2 ml/min/kg 0.9 L/kg 8h 51% GreenScreen Clean Pred. Human Clearance CYP3A4 20 µM Pred. Volume 1.4 L/kg Pred. Terminal half-life biphasic Major metabolite Acyl Glucuronide stability Glucuronide t½ > 4 h PK-PD dose simulation An oral, low dose (<10 mg), once-a-day CRTh2 Antagonist 50 2 ml/min/kg 2-6 mg QD 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-Kinetic Relationships (SKR) are in their infancy and/or qualitative R id Residence Ti Time can b be d designed i d To find Long Residence, you need to look for it 51 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 M t Vives Montse Vi Miriam Zanuy 52 Respiratory Therapeutic Area Mó i Bravo Mónica B 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 Villano a Integrative Pharmacology Clara Armengol Laia Benavent Luis Boix Elena Calama Amadeu Gavaldà B t í Lerga Beatríz L Sonia Sánchez Computational and Structural Ch i t and Chemistry d Bi Biology l Sandra Almer Yolanda Carranza Sònia Espinosa Estrella Lozoya Pathology and Toxicology Ana Andréa Mariona Aulí Cloti Hernández Hernánde Neus Prats Development Cesc Carrera Nieves Crespo Juan Pérez Andrés Juan Pérez García Gemma Roglan Francisco Sánchez Carme Serra Intellectual Property Houda Meliana Eulàlia u à a Pinyol yo Management Paul Beswick Jordi Gràcia Vi t Matassa Victor M t Monste Miralpeix
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