Acrivastine

Absorption

Acrivastine was absorbed rapidly from the combination capsule following oral administration and was as bioavailable as a solution of acrivastine. After administration of SEMPREX-D Capsules, maximum plasma acrivastine concentrations were achieved at 1.14 ± 0.23 hour.

Description

Acrivastine is an orally-active HI .receptor antagonist reportedly useful in the treatment of allergic rhinitis. The main advantages of acrivastine in comparison to older antihistamines are its low sedative potential and the absence of anticholinergic side-effects.

Description

Acrivastine is a histamine H₁ receptor antagonist with a K_i value of 10 nM in COS-7 cells expressing the human receptor. In vivo, acrivastine (1 mg/kg) completely inhibits response to histamine in guinea pigs. Formulations containing acrivastine have been used for the treatment of seasonal allergies and hay fever.

Originator

Burroughs Wellcome (USA)

The Uses of Acrivastine

Acrivastine has been used as an antihistamine to investigate the relation between the increased residence time of antihistamine at the histamine H1 receptor (H1R) and the duration of effective target-inhibition by this antagonist.

The Uses of Acrivastine

Antihistaminic.

What are the applications of Application

Acrivastine is a second-generation antihistamine

Background

Acrivastine is a triprolidine analog antihistamine indicated for the treatment of allergies and hay fever. As an H1 receptor antagonist, it functions by blocking the action of histamine at this receptor thereby preventing the symptoms associated with histamine release such as pruritis, vasodilation, hypotension, edema, bronchoconstriction, and tachycardia.
Acrivastine is currently available in combination with pseudoephedrine as the FDA-approved product Semprex-D.

Indications

For the relief of symptoms associated with seasonal allergic rhinitis such as sneezing, rhinorrhea, pruritus, lacrimation, and nasal congestion.

Definition

ChEBI: A member of the class of pyridines that is (pyridin-2-yl)acrylic acid substituted at position 6 by a [(1E)-1-(4-methylphenyl)-3-(pyrrolidin-1-yl)prop-1-en-1-yl group. It is a non-sedating antihistamine used for treatment of hayfever, urtic ria, and rhinitis.

Manufacturing Process

Butyl lithium (50 ml, 1.65 mol in hexane) was added under nitrogen to a stirred suspension of 2,6-dibromopyridine (19.5 g) in dry ether (200 ml) at - 50°C. After 0.75 h a solution of 4-tolunitrile (10.0 g) in ether (50 ml) was added; stirring was continued at -50°C for 3 h. The mixture was allowed to warm to -30°C and treated with hydrochloric acid (200 ml, 2 mol). The precipitated solid was collected, washed with water to give the 2-bromo-6-(4- toluoyl)pyridine as colourless needles (12.2 g), melting point 97°-98°C (recrystallized from aqueous ethanol). A mixture of 2-bromo-6-(4-toluoyl)pyridine (200.0 g), ethylene glycol (85 ml), p-toluenesulphonic acid (32.0 g) and benzene (11 ml) was boiled under a Dean/Stark trap until water collection had become very slow (about 20 ml collected in 16 h). The cooled solution was poured into ice/water containing sodium carbonate (100.0 g) with stirring. The benzene layer was separated, washed with water, dried with sodium sulfate and evaporated to about 500 ml. Cooling gave a first crop of 2-(6-bromo-2-pyridyl)-2-(4-tolyl)-1,3-dioxolan, melting point 113°-114°C (170.0 g). Dilution with petroleum ether gave a second crop, melting point 109°-112°C (34.0 g). The residue after evaporation (31.0 g) was recycled.
A solution of 2-(6-bromo-2-pyridyl)-2-(4-tolyl)-1,3-dioxolan, vide supra, (70.0 g) in dry toluene (800 ml) was added dropwise during 5 h to a stirred solution of butyl lithium (1.6 mol in hexane, 200 ml) and toluene (200 ml) at -65° to - 72°C under nitrogen. After a further 30 min at -70°C, dry dimethylformamide (40 ml) was added during 35 min. Stirring continued overnight at -70° to - 60°C. Hydrochloric acid (2 N, 400 ml) was added, allowing the temperature to rise to about -10°C. After 30 min, 2 N ammonia (ca. 90 ml) was added to pH 7-8. The toluene layer was separated and the aqueous phase was extracted with ether. The combined organic liquids were washed with ice/water, dried (MgSO4) and evaporated in vacuum below 50°C. The aldehyde, 2-(6-formyl-2- pyridyl)-2-(4-tolyl)-1,3-dioxolan, (63.9 g) crystallized on keeping at 3°C, melting point 52-63°C.
The 2-(6-formyl-2-pyridyl)-2-(4-tolyl)-1,3-dioxolan (2.5 g) was dissolved in 1,2-dimethoxyethane (10 ml) and added to a solution of the phosphonate carbanion produced from triethyl phosphonoacetate (2.0 g) and sodium hydride (0.22 g) in the same solvent. The mixture was stirred for 2 h, diluted with ether (25 ml) and treated with hydrochloric acid (5 ml, 2 mol). The organic phase was separated, washed with water, dried, and evaporated. The resulting oil was dissolved in ethanol (20 ml) containing concentrated hydrochloric acid (3 ml) and water (3 ml). After heating on the steam bath for 10 min, the solution was diluted with ice water, rendered alkaline with sodium bicarbonate solution, and extracted with ether. Evaporation gave 1.0 g ((E)-3- (6-(4-toluoyl)-2-pyridyl)acrylate as colourless platelets, melting point 108°- 111°C (crystallized from cyclohexane).
Butyl lithium (10 ml, 1.64 mol in hexane) was added under nitrogen to a stirred suspension of triphenyl-2-pyrrolidinoethylphosphonium bromide (7.2 g) in dry toluene (75 ml). After 0.5 h, ((E)-3-(6-(4-toluoyl)-2-pyridyl)acrylate, vide supra, (4.8 g) in toluene (50 ml) was added. The suspension, initially orange, became deep purple, then slowly faded to yellow during 2 h heating at 75°C. The cooled solution was diluted with ether (150 ml) and treated with hydrochloric acid (50 ml, 2 mol). The aqueous phase was separated, washed with ether, and basified with potassium carbonate (ice) and extracted with ether. The mixture of isomeric esters obtained by evaporation was dissolved in ethanol (100 ml) containing sodium hydroxide solution (20 ml, 1 mol) and partially evaporated on the steam bath under reduced pressure for 5 min. The residual aqueous solution was neutralized with sulfuric acid (20 ml, 0.5 mol) and evaporated to dryness. The solid residue was extracted with hot isopropanol (3x50 ml) and the extracts were concentrated until crystallization commenced. The (E)-3-(6-(3-pyrrolidino-1-(4-tolyl)prop-1-(E)-enyl)-2- pyridyl)acrylic acid, melting point 222°C (dec. recrystallization from isopropanol) was obtained.

brand name

Semprex

Therapeutic Function

Antihistaminic

General Description

Acrivastine, (E, E)-3-[6-[1-(4-methylphenyl)-3-(1-pyrrolidinyl)-1-propenyl-2-pyridinyl]-2-propenoic acid(Semprex), is a fixed-combination product of the antihistamineacrivastine (8 mg) with the decongestant pseudoephedrine(60 mg). Acrivastine is an odorless, white to pale cream crystallinepowder that is soluble in chloroform and alcohol andslightly soluble in water.
Acrivastine is an analog of triprolidine containing acarboxyethenyl moiety at the 6-position of the pyridylring. Acrivastine shows antihistaminic potency and durationof action comparable to those of triprolidine (Table23.2). Unlike triprolidine, acrivastine does not display significantanticholinergic activity at therapeutic concentrations.Also, the enhanced polarity of this compound resultingfrom carboxyethenyl substitution limits BBBaccumulation, and thus, this compound produces less sedationthan triprolidine.
Limited pharmacokinetic data are available for this compound.Orally administered drug has a half-life of about 1.7hours and a total body clearance of 4.4 mL/min per kilogram.The mean peak plasma concentrations are reported tovary widely, and the drug appears to penetrate the CNSpoorly. The metabolic fate of acrivastine has not beenreported.

Biochem/physiol Actions

Acrivastine is a second-generation antihistamine, an H1-receptor antagonist.

Clinical Use

Acrivastine, an acidic congener of triprolidine in which a carboxylic acid–substituted chain has been attached, also is a second-generation, nonsedating antihistamine. Penetration of the blood-brain barrier is limited, and it is less sedating than triprolidine. It is used principally in a combination with a decongestant.

Drug interactions

Potentially hazardous interactions with other drugs
Antivirals: concentration possibly increased by ritonavir.

Metabolism

Not Available

Metabolism

Acrivastine undergoes metabolism in the liver, and along with an active metabolite, is excreted principally in the urine.