Riociguat

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Riociguat

  1. 1. Claire JagodzinskiLaurent MagniesMélanie Tilte 1
  2. 2. Some words about RIOCIGUAT… First in class New target Direct sGC stimulator Sensitises sGC to NO Vasodilatation Orally treatment of PAH Improves quality of life Currently in clinical trial, phase III 2
  3. 3. PLAN Pathology Treatments sGC Discovery and development of Riociguat Clinical trials 3
  4. 4. Pulmonary Arterial Hypertension WHO classification Orphan disease, 30-50 cases per million Poor prognosis Symptoms: breathlessness, chest tightness, fatigue Vascular proliferation and remodelling Progressive increase in PVR Right ventricular failure, hypertrophy and death Imbalance of vascular effectors N ENGL J MED 351;16 OCTOBER 14, 2004 « PULMONARY ARTERIAL HYPERTENSION » .FARBER ET AL 4
  5. 5. Diagnostic of PAH 4 classes: class I is the least severe and class IV the most advanced PAH symptoms non specific Early diagnostic important 5
  6. 6. Diagnostic of PAH Detection: Echocardiography 6
  7. 7. Diagnostic of PAH• Evaluation: 6-MWT and right heart catheterisationThe patient walks as faras possible in 6 minutes•Safe•Highly reproductible•Inexpensive equipment•Used as primary endpoint in clinical trials ATS. Am J Crit CARE MED 2002 7
  8. 8. PAH associated with HIV 0,5% of HIV-patients (6 to 12 times as high as the general population) related to the duration of HIV infection, due to concomitant infections Mechanism unclear HIV-1 GP120 may stimulate the production of ET by macrophages seems to be independent of the degree of immunosuppression N ENGL J MED 351;16 OCTOBER 14, 2004 « PULMONARY ARTERIAL HYPERTENSION » .FARBER ET AL 8
  9. 9. PAH associated with others conditions Scleroderma = systemic sclerosis : prevalence of PAH is up to 16% PAH is the leading cause of death Very poor prognosis Human herpesvirus N ENGL J MED 351;16 OCTOBER 14, 2004 « PULMONARY ARTERIAL HYPERTENSION » .FARBER ET AL 9
  10. 10. ACTUAL TREATMENTS • Prostacyclin • Endothelin • NO • PDE5 No curative treatment 10
  11. 11. N ENGL J MED 351;14 SEPTEMBER 30, 2004 « TREATMENTOF PAH » HUMBERT ET AL 11
  12. 12. Prostacyclin therapy PGI2 is producted by metabolisation of arachidonic acid Induces relaxation Stimulating AMPc production N ENGL J MED 351;14 SEPTEMBER 30, 2004 « TREATMENT OF PAH » HUMBERT ET AL 12
  13. 13. Epoprostenol Flolan® Intravenous infusion Improvement in 6-MWT Short half-life (3 min) Iloprost Ventavis®  Delivered by inhaler  Short duration of action N ENGL J MED 351;14 SEPTEMBER 30, 2004 « TREATMENT OF PAH » HUMBERT ET AL 13
  14. 14. 14
  15. 15. Endothelin’s actions 15
  16. 16. Antagonists of ET1-R: Bosentan Tracleer® Oral treatment Improvements in 6-MWT No dose-response effect Hepatotoxicity Sitaxsentan and Ambrisentan: selective of Eta Tezosentan N ENGL J MED 351;14 SEPTEMBER 30, 2004 « TREATMENT OF PAH » HUMBERT ET AL 16
  17. 17. 17
  18. 18. Nitric Oxide Vasodilatator Synthetised by NO synthase in endothelial and epithelial cells Inhaled treatments with NO are unsuitable as long term therapies for PH due to: short life, development of tolerance, non specific interactions with biomolecules Toxicity with high dose CHEM MED CHEM 2009 4, 853-865 « DISCOVERY OF RIOCIGUAT » MITTENDORF ET AL 18
  19. 19. PDE5 effects+ 19
  20. 20. Inhibition of PDE5: Sildénafil Revatio® Predominant PDE isoform in the lung that metabolizes cGMP Pulmonary vasodilator effect Oral treatment Increase of cGMP in smooth muscle Improved exercise capacity and pulmonary hemodynamics No evidence of dose-response relationship N ENGL J MED 353;20 NOVEMBER 17, 2005 « SILDENAFIL CITRATE THERAPY FOR PAH » GALIE ET AL 20
  21. 21. Soluble guanylate cyclase Heterodimer: larger α subunit and a smaller haem-binding β subunit Prosthetic haem moiety on the haem binding domain with a reduced Fe2+ sGC GTP cGMP Potentiated by NONATURE REVIEWS 1028 NRD 2038 SEPTEMBER 2006 « NO-INDEPENDENT STIMULATORS AND ACTIVATORS OF SOLUBLE SGC » EVGENOV ET AL 21
  22. 22. + NO sGCGTP cGmP 22
  23. 23. Model of the haem binding domain of human sGC β-subunitNATURE REVIEWS 1028 NRD 2038 SEPTEMBER 2006 « NO-INDEPENDENT STIMULATORS AND ACTIVATORS OF SOLUBLE SGC » EVGENOV ET AL 23
  24. 24. Structure of sGC Cleavage of His N His N 2+ the haem- histidine bond N 2+ N 2+N N Fe N N Fe N Fe N N NO N NO Penta coordinated Hexa coordinated Penta coordinatedhistidyl haem complex histidine-haem-NO nitrosyl-haem intermediate complex Abolition of activation if remove, oxydise or inhibit Changes in the redox state leads to the formation of an NO insensitive form of sGC NATURE REVIEWS 1028 NRD 2038 SEPTEMBER 2006 « NO-INDEPENDENT STIMULATORS AND ACTIVATORS OF SOLUBLE SGC » EVGENOV ET AL 24
  25. 25. NO-sGC-cGMP Signal Transduction Pathway NATURE REVIEWS 1028 NRD 2038 SEPTEMBER 2006 « NO- INDEPENDENT STIMULATORS AND ACTIVATORS OF SOLUBLE SGC » EVGENOV ET AL 25
  26. 26. Differences between systemic and pulmonary circulationIn response to hypoxia : Pulmonary arterial pressure Systemic pressure • Pressure increases in PAs and decreases in renal arteries• Mitochondria alter the production of ROS (·O2ˉ;ONOOˉ), causes the PAs constriction due to the oxidation• Therapies can target the redox 26 EUR RESPIR J 2009; 33: 717-721 « SGC STIMULATORS AS A POTENTIAL THERAPY FOR PAH » E.D. MICHELAKIS
  27. 27. Two novel drug class sGC activators don’t modulate NO signalling at all but activate the NO unresponsive haem oxidized or haem free enzyme NO and haem independentNATURE REVIEWS 1028 NRD 2038 SEPTEMBER 2006 « NO-INDEPENDENT STIMULATORS AND ACTIVATORS OF SOLUBLE SGC » EVGENOV ET AL 27
  28. 28. NATURE REVIEWS 1028 NRD 2038 SEPTEMBER 2006 « NO-INDEPENDENT STIMULATORS AND ACTIVATORS OF SOLUBLE SGC » EVGENOV ET AL 28
  29. 29. sGC Activators By binding the unoccupied haem binding pocket Or by replacing the weakly bound oxidized haem BAY 58-2667 = Cinaciguat Intravenous form Currently in clinical trial 29
  30. 30. Two novel drug class BAY 63-2521: Riociguat sGC stimulators stimulate sGC directly and enhance the sensitivity of the reduced enzyme to low levels of bioavailable NO NO-independent but haem dependent Stabilization of the nitrosyl-haem complex Crucial dependency of Fe2+ NATURE REVIEWS 1028 NRD 2038 SEPTEMBER 2006 « NO-INDEPENDENT STIMULATORS AND ACTIVATORS OF SOLUBLE SGC » EVGENOV ET AL 30
  31. 31. NATURE REVIEWS 1028 NRD 2038 SEPTEMBER 2006 « NO-INDEPENDENT STIMULATORS AND ACTIVATORS OF SOLUBLE SGC » EVGENOV ET AL 31
  32. 32. DISCOVERY AND OPTIMIZATION 32
  33. 33. • 1994: HTS which induce an increase of NO synthesis andstimulate sGC• Led to 5-Substituted-2-furaldehyde-hydrazone• sGC stimulator• Increase when exposed to light, which is unwanted • Dec 1994: Ko and co-workers described indazole derivative YC-1 CHEM MED CHEM 2009 4, 853-865 « DISCOVERY OF RIOCIGUAT » MITTENDORF ET AL 33
  34. 34. Chemical optimization Based on YC-1 Similar mode of action but (2) and (3) are more potent and more specific of PDEActivity worn by 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine 34 CHEM MED CHEM 2009 4, 853-865 « DISCOVERY OF RIOCIGUAT » MITTENDORF ET AL
  35. 35. In vitro assays and isolated organs cGMP formation in a sGC overexpressing Chinese hamster ovarian cell line Inhibition of contractions induced by phenylephrine on rabbit aortic rings 35 CHEM MED CHEM 2009 4, 853-865 « DISCOVERY OF RIOCIGUAT » MITTENDORF ET AL
  36. 36. Activity of (2) and (3) (2): significant decrease of pulmonary arterial pressure, reversal in right ventricular hypertrophy, but induction of CYP450 (3): no relevant CYP interaction because of the more polar morpholine substituent, unfavorable PK profile 36 CHEM MED CHEM 2009 4, 853-865 « DISCOVERY OF RIOCIGUAT » MITTENDORF ET AL
  37. 37. Actions on PDE YC-1: Inhibits PDE 5 with IC-50 of 10µM. BAY 41-2272 (2): No relevant inhibition of PDE 1,2,5,9 up to 10mM. BAY 41-8543 (3): No PDE inhibition at pharmacologically relevant concentration.NATURE REVIEWS 1028 NRD 2038 SEPTEMBER 2006 « NO-INDEPENDENT STIMULATORS AND ACTIVATORS OF SOLUBLE SGC » EVGENOV ET ALCHEM MED CHEM 2009 4, 853-865 « DISCOVERY OF RIOCIGUAT » MITTENDORF ET AL 37
  38. 38. SAR 38
  39. 39.  Activity worn by 1-(2-fluorobenzyl)-1H-pyrazolo[3,4- b]pyridine R3-R1: NH2: diamino analogues display a slightly more potent relaxation of rabbit aorta and positive impact of the amino group on oral exposure. R2: pyrimidin C5 : No clear SAR demonstrated on CYP 1A2 et 3A4, wide range of polars substituants and lipophilic groups. CHEM MED CHEM 2009 4, 853-865 « DISCOVERY OF RIOCIGUAT » MITTENDORF ET AL 39
  40. 40. 40CHEM MED CHEM 2009 4, 853-865 « DISCOVERY OF RIOCIGUAT » MITTENDORF ET AL
  41. 41. (12) and (20) are derivated from(3) because of its no relevantCYP interaction CHEM MED CHEM 2009 4, 853-865 « DISCOVERY OF RIOCIGUAT » MITTENDORF ET AL 41
  42. 42. (20): RiociguatResults for female Beagle dogs: R2 = N-méthylcarbamate Freatest PK profile Selected as a drug development candidate 42 CHEM MED CHEM 2009 4, 853-865 « DISCOVERY OF RIOCIGUAT » MITTENDORF ET AL
  43. 43. CYP and PDE profile  No significant effects on CYP 1A2, 2B6, 2C19, 3A4  Not dose-dependent  BAY 63-2521: IC-50 values for PDE 2,3,4,5,8,9 are > 10µM.PATENT US 2006/0052397A1 Mar. 9,2006 CARBAMATE-SUBSTITUTED PYRAZOLOPYRIDINES 43
  44. 44. SYNTHESE 44
  45. 45. F F F F CN TFA NH3, MeOH O TFA + H2N N 3-dimethylamine N N N N HN N N N CO2Et acroleine NH2 condensation aminolyse CO2Et cyclo- CO2Et CONH2 F F condensation TFAA, Py NaOMe, MeOH N N N N N N Pinnerdeshydratation CN NH2 HN F F F N NC CN NaOMe, DMF N N N Ni Raney N + N N 110°C N N NNPh NH2 cyclo- N reduction malonitrile N N HN N addition NH2 NH2 H2N H2N NNPh NH2 Methyl-4,6-diamino-2-(1-(2-fluorobenzyl)-1H-pyrazolo [3,4-b]pyrydin-3-yl)-pyrimidin-(-ylmethylcarbamate) carbamate deprotonation methylation CHEM MED CHEM 2009 4, 853-865 « DISCOVERY OF RIOCIGUAT » MITTENDORF ET AL 45
  46. 46. In vivo experiments Models of PAH Mice exposed to chronic hypoxia (10% O2) in a ventilated chamber Rats with 60 mg.kg-1 monocrotaline subcutaneously injection EUR RESPIR J 2008; 32: 881-891 « EXPRESSION AND FUNCTION OF SGC IN PAH » SCHERMULY ET AL 46
  47. 47. Mice in chronic hypoxiaRight ventricular systolic pressure Right ventricular systolic pressure Systemic arterial pressure Cardiac frequency 47 EUR RESPIR J 2008; 32: 881-891 « EXPRESSION AND FUNCTION OF SGC IN PAH » SCHERMULY ET AL
  48. 48. Hypertensive rats Dose dependent blood pressure decrease Single dose 48
  49. 49. CLINICAL TRIALS 49
  50. 50. Clinical trial, phase I 58 healthy male volunteers Single oral dose 0,25 to 5mg or placebo No serious adverse events Effect increased dose dependently at doses of 1mg to 5mg Mean arterial and diastolic pressures were decreased at doses of 1mg and 5mg Systolic pressure not significantly affected 50
  51. 51. Pharmacokinetics (1) n=15 persons Riociguat plasma concentration Riociguat plasma concentrations following a single oral dose of 1mg and 2,5mg Changes in PVR from baseline (dose dependent increase whith pronounced interindividual variability) EUR. RESPIR.J.2009; 33: 785-792 « FIRST ACUTE HAEMODYNAMIC STUDY OF sGC 51 STIMULATOR RIOCIGUAT IN PH » F.GRIMMINGER AND COWORKERS
  52. 52. Pharmacokinetics (2) n=5 in 1mg dose group and n=10 in 2,5mg dose group Vz/f: apparent volume of distribution during terminal phase after oral administration CL/f: total body clearance of drug from plasma calculated after oral administration  Peak concentration after 0.25-1.5h  Half-life of 10-12h  Dose proportionnality for the both doses (AUC and Cmax): factor dose had no influence on either parameters  No hepatotoxicity, no abnormalities in laboratory values 52EUR. RESPIR.J.2009; 33: 785-792 « FIRST ACUTE HAEMODYNAMIC STUDY OF sGC STIMULATOR RIOCIGUAT IN PH » F.GRIMMINGER AND COWORKERS
  53. 53. Clinical trial, phase II  During 12 weeks, 3 times a day, orally  75 patients with PAH disease  PVR>300 dyn.s.cm-1  Evaluation of safety and tolerability: dose<2,5mg had no clinically relevant effects on vital signs, electrocardiograms, laboratory values and blood gasesEUR. RESPIR.J.2009; 33: 785-792 « FIRST ACUTE HAEMODYNAMIC STUDY OF sGC STIMULATOR RIOCIGUAT IN PH » F.GRIMMINGER AND COWORKERS 53
  54. 54. Pharmacodynamics mean pulmonary arterial pressure pulmonary vascular resistance systemic vascular resistance systolic blood pressure  No pulmonary selectivity, but systemic vasodilatation not accompagnied by any relevant side-effect 54EUR. RESPIR.J.2009; 33: 785-792 « FIRST ACUTE HAEMODYNAMIC STUDY OF sGC STIMULATOR RIOCIGUAT IN PH » F.GRIMMINGER AND COWORKERS
  55. 55. Clinical trial, phase II Evaluation of exercise capacity with 6MWT Strong and significant improvements in pulmonary hemodynamics  Improvement score in 6-MWT after 14 days (+73,5% after 12 weeks)  Well tolerated, favorable safety profile http://www.investor.bayer.com/en/ 55
  56. 56. CONCLUSION Clinical trial, Phase III First results are expected in 2011 Trials: - PAH: Pulmonary Arterial Hypertension sGC- Stimulator Trial = PATENT - Chronic Thromboembolic Pulmonary Hypertension (CTEPH): Chronic Thromboembolic Pulmonary Hypertension sGC-Stimulator Trial = CHESTGHOFRANI HA. sGC STIMULATION: AN EMERGENING OPTION IN PAH THERAPY ORAL PRESENTATION AT THE EUROPEAN RESPIRATORYSOCIETY CONGRESS, BERLIN, GERMANY; OCTOBER 4-8 2008GHOFRANI HA AND CO RIOCIGUAT TREATMENT IN PATIENTS WITH CTEPH OR PAH. POSTER PRESENTATION AT THE AMERICAN THORACIC SOCIETY 56INTERNATIONAL CONFERENCE, 15-20 MAY 2009, SAN DIEGO, CALIFORNIA, USA
  57. 57. http://www.investor.bayer.com/en 57

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