1 / 15

Macitentan – A novel sulfamide

Macitentan – A novel sulfamide. Bosentan. Macitentan. 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

vporter
Download Presentation

Macitentan – A novel sulfamide

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Macitentan – A novel sulfamide Bosentan Macitentan Bolli M, et al. J Med Chem 2012; 55:7849-61.

  2. 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.

  3. 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

  4. Optimisation of the physicochemical properties compared to Bosentan may favour macitentan’s penetration into tissues: Log D Log D (Distribution coefficient) Lipid:Aqueous In vitro data Macitentan 800:1 Bosentan 20:1 Ambrisentan 1:2.5 Blood Membrane Tissue • 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. *To date, no head-to-head trials in humans have been performed.

  5. Macitentan displays sustained binding to its target receptors Experimental system: Determination of changes in inhibitory potency after antagonist wash-out (calcium flux in PASMC) In vitro data Ambrisentan Macitentan Bosentan 1000 Kb after washout (nM) * * * * * * * * 100 * * * * 10 t1/2~70 sec t1/2~40 sec * * * 1 t1/2~17 min * * 0.1 0 20 60 40 60 40 20 0 40 0 60 20 Time after wash-out (minutes) Time after wash-out (minutes) Time after wash-out (minutes) Macitentan displays a 15-fold increased receptor residence time (t1/2) compared to ambrisentan and bosentan *p < 0.05 Gatfield J, et al. PloS One 2012; 7(10):e47662.

  6. 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 In vitro data 10000 nM 1000 nM 100 nM 10 nM 1 nM Bosentan Ambrisentan Macitentan 0 nM 120 100 80 Normalised IP1 conc. (%) 60 x x x x x x x x 40 x 20 0 -11 -11 -11 -10 -10 -10 -9 -9 -9 -8 -8 -8 -7 -7 -7 -6 -6 -6 -5 -5 -5 ET-1 (log M) ET-1 (log M) ET-1 (log M) 2 nM 500 nM Inactive IC50 20 nM 3000 nM Inactive 1 nM 5 nM 5 nM Protection against high ET-1 X  X Gatfield J, et al. PloS One 2012; 7(10):e47662.

  7. Chronic† macitentan administration reduced mPAP at a dose 10-fold lower than bosentan in the MCT rat model Animalmodel +++ MCT (monocrotaline) * 40 Control *** 30 MCT + macitentan ** *** mPAP (mmHg) *** MCT + bosentan *** 20 *** +++p < 0.001 vs. control * p< 0.05 vs. MCT + vehicle ** p< 0.01 vs. MCT + vehicle 10 *** p< 0.001 vs. MCT + vehicle Veh 0.3 3 10 30 100 300 Dose (mg/kg/day) Iglarz M, et al. J Pharmacol Exp Ther 2008; 327:736-45. †Administered for 4 weeks

  8. Chronic† macitentan administration reduced RV hypertrophy at a dose 10-fold lower than bosentan in the MCT rat model Animalmodel +++ MCT (monocrotaline) 0.5 Control * ** 0.4 ** MCT + macitentan RV/LV+S MCT + bosentan 0.3 +++p < 0.001 vs. control *** *** *** * p< 0.05 vs. MCT + vehicle ** p< 0.01 vs. MCT + vehicle 0.2 *** p< 0.001 vs. MCT + vehicle Veh 0.3 10 30 100 300 3 Dose (mg/kg/day) RV: right ventricular†Administered for 4 weeks Iglarz M, et al. J Pharmacol Exp Ther 2008; 327:736-45.

  9. Effect of macitentan on survival in the MCT rat model of PAH Animalmodel 100 83% 80 p = 0.002 60 Survival (%) 50% 40 Control Monocrotaline (MCT) + vehicle 20 MCT + macitentan* 0 0 7 14 21 28 35 42 Time (days) Iglarz M, et al. J Pharmacol Exp Ther 2008; 327:736-45. Raja SG. Curr Opin Investig Drugs 2010;11:1066-73. *macitentan was administered at 30 mg/kg/day

  10. Macitentan added to ambrisentan leads to a further reduction in MAP Animalmodel **p < 0.05 vs. Ambrisentan then vehicle Ambrisentan then vehicle Ambrisentan then Ambrisentan Ambrisentan then Macitentan 0 -10 -20 Delta MAP (mmHg) -30 p = ns -40 ** -50 Dahl-S rats (n = 5), telemetry equipped Dose: 30 mg/kg (ambrisentan or macitentan) by gavage Iglarz M, et al. Eur Respir J 2012; 40: Suppl. 56:717s.

  11. Addition of ambrisentan to macitentan did not lead to further reductions in MAP Animalmodel Macitentan then vehicle Macitentan then Ambrisentan 0 -10 -20 Delta MAP (mmHg) -30 -40 p = ns -50 Dahl-S rats (n = 5), telemetry equipped Dose: 30 mg/kg (ambrisentan or macitentan) by gavage Iglarz M, et al. Eur Respir J 2012; 40: Suppl. 56:717s.

  12. Macitentan added to bosentan leads to a further reduction in MAP Animalmodel **p < 0.05 vs. Bosentan then vehicle Bosentan then vehicle Bosentan then bosentan Bosentan then macitentan 0 -10 -20 Delta MAP (mmHg) p = ns -30 -40 ** -50 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 Iglarz M, et al. Eur Respir J 2012; 40: Suppl. 56:717s.

  13. Addition of bosentan to macitentan did not lead to further reductions in MAP Animalmodel Macitentan then vehicle Macitentan then bosentan 0 -10 -20 Delta MAP (mmHg) -30 -40 p = ns -50 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 Iglarz M, et al. Eur Respir J 2012; 40: Suppl. 56:717s.

  14. 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 • Fattinger K, et al. ClinPharmacolTher2001; 69:223-31. • 2. Raja SG. CurrOpinInvestig Drugs 2010; 11:1066-73.3. Bolli M, et al. J Med Chem2012; 55:7849-61. • 4. Bruderer S, et al. AAPS 2012; 14:68-78.

  15. 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

More Related