Monday, October 17, 2016

Seratrodast | Thromboxane A2 (TXA2) Receptor Antagonist | Prostaglandin H2 (PGH2) Receptor Antagonist | Treatment of Asthma

Seratrodast [7-Phenyl-7-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dien-1-yl)heptanoic acid] is a thromboxane A2 (TXA2) receptor {TP receptor} antagonist marketed as an antiasthmatic drug with inhibitory effects on immediate asthmatic reaction in asthma and airway hypersensitivity. It also has antagonistic effects on contractile prostanoids, including PGH2, PGF, PGD2, and 11β- PGD2. Thus this drug is expected to have a wide range of antagonistic effects on bronchoconstriction mediators [1, 2].

2D and 3D Structure for Seratrodast

Chemically, it is a quinone derivative with a long alkyl chain ending in a carboxylic acid, making it poorly soluble in water. It is a chiral molecule, though marketed as a racemate, studies report the best activities in the following order of descent: R–enantiomer, racemate and finally S–enantiomer. It is a novel design, orally active, potent and long acting TP/PGH2 receptor antagonist.
Seratrodast does not affect thrombus formation, time to occlusion and bleeding time. Seratrodast has no effect on prothrombin time and activated partial thromboplastin time, thus ruling out any action on blood coagulation cascade [1].
It was the first TP receptor antagonist that was developed as an anti-asthmatic drug and received marketing approval in Japan in 1997. Seratrodast is currently marketed in Japan, China and India (approved in December 2012) as an add-on controller therapy in the management of asthma.

Pharmacological Importance of Thromboxane and Prostaglandin
Thromboxane (TX) A2 and prostaglandin (PG) I2 (prostacyclin) are two of the metabolites of arachidonic acid produced through the cyclooxygenase pathway. These two compounds produce potent but opposite effects on smooth muscle and on platelets. Thromboxane A2 (TXA2) is a type of thromboxane that is produced by activated platelets and has prothrombotic properties: it stimulates activation of new platelets as well as increases platelet aggregation. Prostacyclin (also called prostaglandin I2 or PGI2) is a prostaglandin member of the eicosanoid family of lipid molecules. It inhibits platelet activation and is also an effective vasodilator [3].
The production of thromboxane and/or prostacyclin has been altered in patients with various diseases, such as unstable angina, glomerular disease secondary to systemic lupus erythematosus, systemic sclerosis complicated by Raynaud’s phenomenon, septic shock, and asthma. Increased levels of TXA2 metabolites have been found in the urine and in bronchoalveolar lavage fluid of atopic asthmatics after allergen challenge. These data suggest that treatment with an agent that inhibits TX synthesis or blocks TX receptors could have beneficial effects in these pathologies.
Seratrodast blocks the broncho-constrictor effects of prostaglandins in the body. Seratrodast also decreases the inflammation by antagonising the thromboxane A2 receptor. Addition of a TXA2 receptor antagonist to conventional antiasthma medications may be considered in the management of patients with mild to moderate asthma having increased airway secretions.

Mechanism of Action
Seratrodast, a quinone derivative, is a novel, potent, orally active, and long acting TXA2/PGH2 receptor antagonist. In addition, Seratrodast has PGF, PGD2, and 9α, 11β -PGF2 antagonistic effects [1, 4].
The specificity of Seratrodast at antagonizing the TXA2 receptor was tested in vitro, ex vivo, and in vivo. Because of the short half-life of TXA2 (about 30 s), more stable analogs such as U-46619 and U-44069 were used to study the antagonistic effect of Seratrodast on TXA2 receptors. Similar to TXA2, such analogs exert a potent platelet-aggregating and smooth muscle contracting effect. Several studies in animals were conducted to investigate the pharmacological effects of Seratrodast in these areas and its antagonistic effect on the TXA2 receptor.
The specific binding of Seratrodast to platelets was tested in guinea pigs and humans. Seratrodast inhibited the specific binding of [3H]U-46619 to washed guinea pig platelets with an IC50 value of 0.0082 uM. This inhibition was more effective than the inhibition produced by unlabeled U-46619 (IC50 = 0.037 uM). Moreover, the antagonistic effect of Seratrodast was tested on the human TXA2 receptor genetically introduced into Chinese hamster ovary (CHO) cells. Seratrodast competitively inhibited the specific binding of TXA2 mimic ( [3H]U-46619) to the ovary cells with an IC50 of 0.06 uM, indicating that the drug is an antagonist of human TXA2 receptor [1, 4].
Seratrodast had neither an anti- Leukotriene D4 (LTD), nor an anti- platelet-activating factor (PAF) activity at 100 uM (guinea pig lung membranes) or 10 uM (rabbit platelets), respectively.
The specific antagonism of Seratrodast against the different enzymes involved in arachidonic acid metabolism was also tested. Seratrodast inhibited the production of 5-hydroxyeicosatetraenoic acid from arachidonic acid (5-lipoxygenase antagonism) by rat basophilic leukemia cells with an IC50 value of 0.21 uM. A very weak inhibitory effect of Seratrodast was reported on thromboxane synthetase (horse platelet, 13% inhibition at 10 uM) and cyclooxygenase (bovine vesticular gland, 20% inhibition at 100 uM).

Dosages and Approvals
Seratrodast (Tradename: Bronica) was approved in Japan in 1997 for treatment of bronchial asthma at once daily doses of 80 mg to be administered after dinner. Subsequently China and India (in 2012) have approved the drug an add-on controller therapy in the management of asthma. Seratrodast has been well tolerated following repeated once daily oral doses of up to a maximum of 320 mg. In elderly patients it is recommended that the treatment should be started with a lower dose of 40 mg/day. Phase trials were carried out in the west but it has not been approved by EU or US till date.

Seratrodast was discovered, developed and launched by Takeda Pharmaceuticals, Japan.

Reported Activities for Seratrodast
Platelet Aggregation: In the in vitro studies, Seratrodast inhibited the aggregation of guinea pig platelets induced by a prostaglandin endoperoxide (PGH,) analog, U-44069, arachidonic acid, or collagen in a concentration-dependent manner with IC50 values of 0.31, 0.49 and 0.23 uM respectively. Seratrodast did not affect the platelet activating factor (PAF) or adenosine-5’-diphosphate (ADP)-induced aggregation. Seratrodast at a concentration of nearly 900 uM did not induce shape change or platelet aggregation, indicating that it has no agonistic action.
In ex vivo experiments, Seratrodast by oral administration (0.1-1.0 mg/kg) inhibited in a dose-dependent manner the platelet aggregation induced by U-44069 in guinea pigs and the rabbit platelet aggregation induced by arachidonic acid [1].
Antithrombotic effect:  The activity of Seratrodast was also tested in male New Zealand rabbits were common carotid artery thrombosis induced by endothelial damage was significantly inhibited by oral administration of seratrodast. Seratrodast had little effect (16%) on increased plasma concentration of 11-dehydro TXB2 a stable metabolite of TXA2.
The in vivo antithrombotic effect of Seratrodast was significantly correlated (p < 0.01) with its ex vivo inhibitory effects on arachidonic acid-induced platelet aggregation in rabbits. This correlation suggests that Seratrodast produce its antithrombotic effect by inhibiting the binding of TXA2 to the receptor [1].
The prothrombin time and activated partial thromboplastin time were not affected by high doses of Seratrodast (10 mg/kg), ruling out any direct inhibition of blood coagulation cascade.
Vascular Smooth Muscle: Seratrodast competitively inhibited the contractile response to U-46619 in guinea pig lung parenchymal strips and dog saphenous vein strips with pA2 mean values of 8.29 ± 0.09 and 6.79 ± 0.05, respectively. Similarly, Seratrodast competitively inhibited the contraction of rabbit aorta and pig coronary arteries induced by U-44069 with pA2 values of 8.3 and 9.0, respectively. Seratrodast also inhibited the contraction of rabbit aorta induced by PGF (pA2 = 7.8) and the contraction of pig coronary arteries induced by PGF, PGD2, and 9α, 11β -PGF2 a metabolite of PGD2 with pA2 values of 7.8, 8.6, and 7.8, respectively [1].
Airway bronchoconstriction and asthma: Seratrodast competitively inhibited the contractile response to U-46619, PGD2, and 9α, 11β -PGF2 or PGF with pA2 values of 7.69, 7.20, 7.79, and 5.71, respectively. The contractile responses of guinea pig tracheal strips to leukotriene D4 (LTD4) or platelet activating factor (PAF) were not inhibited by Seratrodast. Seratrodast given orally inhibited the bronchoconstriction in guinea pigs induced by U-46619 (10 ug/kg, i.v.), LTD4 (10 ug/kg i.v.), or PAF (1 ug/kg i.v.). Seratrodast did not inhibit bronchoconstriction induced by histamine (10 ug/kg i.v.) in guinea pigs [1].
The effects of racemic Seratrodast and its enantiomers were compared in vitro and in vivo. In vitro, racemic Seratrodast and the R (+)-enantiomer were more potent than the S(-)-enantiomer. Also, oral administration of racemic Seratrodast and the R(+) enantiomer showed very potent inhibitory effects on U-46619-induced bronchoconstriction in guinea pigs in vivo (minimum effective dose (MED] = 0.3 mg/kg), whereas the S(-)-enantiomer was much less active (MED = 20 mg/kg).

Activities for racemic Seratrodast, R-enantiomer and S-enantiomer

pA2 (Inhibiting U-44069-induced contractions of rabbit aorta) = 8.28, 8.60 and 6.64
pA2 (Inhibiting U-46619-induced contraction of the guinea pig lung) = 8.29 ± 0.09, 8.80 ± 0.10 and 6.53 ± 0.09
IC50 (Inhibition of U-44069-induced aggregation of guinea pig platelets) = 0.35, 0.12 and 13 uM
IC50 (Inhibiting specific binding of [3H]U-46619 to guinea pig platelets) = 0.0074, 0.0021 and 0.21 uM


Common name: AA-2414; AA2414; AA 2414; ABT-001; A-73001; Abbott-73001; Seratrodast
Trademarks: Bronica
Molecular Formula: C22H26O4
CAS Registry Number: 112665-43-7; 103187-09-3 (R-isomer); 103196-89-0 (S-isomer)
CAS Name: 7-phenyl-7-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dien-1-yl)heptanoic acid
Molecular Weight: 354.44
InChI: InChI=1S/C22H26O4/c1-14-15(2)22(26)20(16(3)21(14)25)18(17-10-6-4-7-11-17)12-8-5-9-13-19(23)24/h4,6-7,10-11,18H,5,8-9,12-13H2,1-3H3,(H,23,24)
Mechanism of Action: Thromboxane A2 (TXA2) receptor antagonist; Prostaglandin H2 (PGH2) receptor antagonist
Activity: Management of asthma; Anti-asthmatic drug; Anti-inflammatory; Non-antihistaminic
Status: Launched 1997 (Japan)
Chemical Class: Small molecules; Benzene containing; Carboxylic acid containing; Long chain alkyls; Quinone derivative
Originator: Takeda Pharmaceuticals/Abbott Pharma
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