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_2α, 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_2α, 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_2α (pA₂ = 7.8) and the contraction of pig coronary arteries induced by PGF_2α, 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_2α 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

Summary

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

SMILES:O=C(O)CCCCCC(C1=CC=CC=C1)C2=C(C)C(C(C)=C(C)C2=O)=O

InChI Key: ZBVKEHDGYSLCCC-UHFFFAOYSA-N

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

Seratrodast Synthesis

J Med Chem 1989, 32(9), 2214 – 2221: This is the first reported synthesis for Seratrodast and its various analogous. The article also reports various activities for the compounds. It is most cited reference for Seratrodast synthesis.

Seratrodast-Synthesis-Scheme1

Friedel–Crafts acylation of benzene with the acid chloride from monomethyl pimelate leads to the keto acid. The ketone is then reduced to the alcohol with borohydride; saponification affords the corresponding hydroxyl acid. Treatment of that intermediate with the hydroquinone in the presence of boron trifluoride probably results initially in loss of the hydroxyl group to form the benzylic carbocation. This then attacks the electron-rich hydroqinone ring to form the coupling product. The newly added ring oxidizes to a quinone either in the course of the reaction or on workup to afford Seratrodast. Also see Ref. 6.

Chem. Asian J. 2010, 5, 941 – 945: Treatment of cyclic 1,3-diketone with ethanol in the presence of indium triflate, In(OTf)₃, provided keto ester in 85% yield. Carboxylic acid was yielded in 84% yield by the reduction of keto ester with sodium borohydride and hydrolysis of the formed alcohol. After the condensation of alcohol with 2,3,5-trimethylbenzene-1,4-diol in the presence of a boron trifluoride–diethyl ether complex followed by oxidation, Seratrodast was obtained in 61% yield.

Seratrodast-Synthesis-Scheme2

Identifications:

1H NMR (Estimated) for Seratrodast

Experimental: To be filled later.

Sideeffects: The most commonly reported adverse reaction (AEs) by less than 5% participants include rash, itching, dysgeusia, anemia, eosinophilia, drowsiness, headache, dizziness, lightheadedness, palpitations and fatigue. Very rare or uncommon AEs include hot flashes, edema, insomnia, tremor, numbness, thrombocytopenia, nose bleeding, vomiting and bleeding tendency of subcutaneous hemorrhage.

Intake of Seratrodast can result in severe liver dysfunction with elevated AST (GOT), ALT (GPT). Few cases of jaundice in participants are also reported (0.2%). Also, fulminant hepatitis (in less than 0.1% participants) has been reported. Carefully monitoring, such as performing a liver function tests on a regular basis (once a month) is suggested. If any abnormalities are observed, administration should be discontinued with appropriate treatment.

The starting dosage in elderly is 40 mg with regular liver function checks. Though there are no reports on safety during pregnancy but Seratrodast should be avoided by lactating mothers. Pregnant women should be prescribed only if the therapeutic benefit is determined to exceed the risk.

Seratrodast has never been tried and approved for pediatrics use.

Others: A computational docking study is reported using the crystal structure of Seratrodast with a model for the human receptor (TXA₂). The human TXA₂ receptor was constructed on the basis of its amino acid sequence [7]. The approach though is qualitative but was able to prove the binding of the R isomer (total energy = -73.10 kcal/mol) to the TXA₂ receptor is favored with respect to the binding of the S isomer (total energy = -70.21 kcal/mol). As, this was consistent with biological data, hence the binding model was used as starting point to docking studies of new antagonists within the aryl sulfonamide family with the modeled human TXA₂ receptor.

A generic drug manufacture in India has published computational docking pictures for Seratrodast with TXA₂ from Indian gene pool. No results are shared other than that Seratrodast is suitable for Indian people (here). No binding energies results are shared. Moreover, the difference between TXA₂ from Indian gene pool v/s that from Japanese or European gene pool is not described. It appears to be an in-house effort with everything to hide and nothing to share.

References:

1. Samara, E. E. Seratrodast (AA-2414)-A Novel Thromboxane-A, Receptor Antagonist. Cardiovascular Drug Reviews 1996, 14(3), 272 - 285. (FMO only)

2. Horiguchi, T.; et. al. Study on the Usefulness of Seratrodast in the Treatment of Chronic Pulmonary Emphysema. Drug Res 2002, 52(10), 764 - 768. (FMO only)

3. Prostaglandins and Thromboxanes. Butterworths Monographs in Chemistry. Butterworth and Co (Publishers) Ltd, 1982. (FMO only)

4. Shiraishi, M.; et. al. Quinones. 4. Novel eicosanoid antagonists: Synthesis and pharmacological evaluation. J Med Chem 1989, 32(9), 2214 - 2221. (FMO only)

5. Kuninobu, Y.; et. al. Indium-Catalyzed Synthesis of Keto Esters from Cyclic 1,3-Diketones and Alcohols and Application to the Synthesis of Seratrodast. Chem. Asian J. 2010, 5, 941 – 945. (FMO only)

6. Lednicer, D. Drugs based on a substituted benzene ring. Chap. 2: Strategies for Organic Drug Synthesis and Design, Second Edition. John Wiley & Sons, Inc., 2009. (FMO only)

7. Wouters, J.; et. al. Antagonism of the txa2 receptor by seratrodast : a structural approach. Bioorg Med Chem Lett 1999, 9, 2867 – 2870. (FMO only)

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