Tazarotene

Description

Tazarotene belongs to a third generation prescription topical retinoid. It is marketed in different forms including cream (brand name: Avage), foam (brand name: Fabuir) and gel (brand name: Tazorac). It is mainly used for the treatment of psoriasis, acne, and sun damaged skin. The detailed mechanisms of action of Tazarotene are still unclear. It is converted to its active form, the cognate carboxylic acid of tazarotene (AGN 190299) in vivo through rapid de-esterification in animals and man. AGN 190299 is capable of binding to all the three members of the retinoic acid receptor (RAR) family: RARα, RARβ, and RARγ with relative selectivity for RARβ, and RARγ. This process may further modify gene expression. However, it is unclear whether this is related to its mode of action. Common side effects associated with it include worsening of acne, desquamation, burning/stinging, erythema and pruritus increased sensitivity to sunlight, dry skin, itchiness, redness, skin pain rash and skin discoloration. In most cases, these side effects are mild and can remarkable decrease after the first 2–4 weeks. Tazarotene should not be used in the following cases: patients are allergic to it; patients are pregnant; patients have a sunburn; patients are taking photo-sensitive drugs such as thiazides and tetracycline.

Dermatology drugs

Tazarotene belongs to the third generation retinoid dermatology drug and is also the retinoid A-like prototype for skin tropical administration and has regulatory effect on epidermal cell differentiation and proliferation. It is mainly used for the treatment of plaque psoriasis vulgaris. Tazarotene cream can also be used for the treatment of facial acne. The clinical administrated product contains an active ingredient of this product being 15mg/30g with its gel being subject to tropical administration. At half an hour before sleep every night, apply appropriate amount of this product into the wounded part. Before treatment, first clean the affected area and apply the drug evenly to the skin lesion part after the dry of the skin for forming a thin film; after applying the drug, the patients should gently rub in order to promote the absorption of drugs. Pea-sized gel can cover a palm-size area of ​​skin lesions. The application area should not exceed 20% of body surface area. Wash hands with soap after rubbing the drug.
Psoriasis is a common benign, acute or chronic inflammatory skin disease. It occurred on the basis of genetic predisposition. Trauma or irritation of normal skin can induce the occurrence of psoriasis lesions (Koebner phenomenon): There are several different manifestations of psoriasis-the most common is plaque type. Rash type (guttate) psoriasis includes a lot of 3~10mm skin lesions. It may occasionally occur after mental stress or streptococcal pharyngitis. Seriously, there may be occasionally life-threatening forms such as generalized pustular and erythrodermic psoriasis. Sudden onset of plaque type or generalized erythrodermic psoriasis may be associated with HIV infection.
Tazarotene gel belongs to the topical formulations of formic acid and can be used for the treatment of psoriasis. Early research has shown that: twice daily for topical administration of eight weeks with about 50% patients with mild to moderate psoriasis having at least 75% of their lesions be alleviated. But the completely eliminated plaque number accounts for less than 10%. Tazarotene gel accounts for concentrations of 0.05% and 0.1%. There is no difference on the efficacy of topical administration of 0.1% gel once per day or twice per day. However, tropical administration of the 0.5% gel once per day gives a poor efficacy.
Tazarotene, as a synthetic ethylene retinal, after topical application, it can be quickly converted to tazarotene acid and plays the pharmacological effects. Tazarotene acid, after binding to the skin retinoid acid receptor-γ (RAR-γ), it can achieve the purpose of alleviating the clinical symptoms through restoring to normal skin differentiation and reducing the inflammation of the skin.

Adverse reactions and precautions

Adverse reactions of tazarotene mainly include skin reactions, manifested as itching, burning, stinging, redness, irritation, skin irritation, scaling, dermatitis, chapped, edema, bleaching, drying and bleeding.
Precautions:
1. For women of childbearing age, within the first 2 weeks before the start of tazarotene gel treatment, we need to perform serum or urine pregnancy test to confirm that the pregnancy test is negative. Start the treatment at the secondary day or third day in the next normal menstrual cycle. Before treatment, during treatment and for some time after cessation of treatment, the patients must use effective contraceptive methods.
2. Avoid contact between drug and eyes, mouth and mucous membrane; try to avoid the contact between skin and the drug. In case of contact with eyes, rinse thoroughly with water.
3. In cases of skin irritation such as itching, try not to scratch and can apply with a small amount of emollient; in severe case, you should stop using this drug or administer at the next day.
4. This product is not recommended for treating acute eczema.
5. During the treatment, avoid excessive exposure to the sun. You should also avoid simultaneously administration of taking photosensitive drug.
6. After application of the drug, avoid using clothing and bandaging for affected area. You should avoid using pharmaceuticals and cosmetics which can dry the skin. Safety information regarding to the applied area should not exceed 20% of the body surface area has not been established.
7. It should be contraindicated in pregnant and lactating women. For this drug, patients allergic to other aldehydes retinol or vitamin A derivative should be tabooed.
8. Safety and efficacy regarding to the children under age 12 for using tazarotene has not been established.
The above information is edited by the chemicalbook of Dai Xiongfeng.

Chemical Properties

It is as white-like or pale yellow solid.

References

https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020600s008lbl.pdf
https://en.wikipedia.org/wiki/Tazarotene
http://www.rxlist.com/tazorac-drug/side-effects-interactions.htm

Chemical Properties

White Solid

Originator

Avage,Allergan

Uses

Used to treat psoriasis, acne and sun damaged skin.

Uses

An acetylenic retinoid prodrug converted to the active metabolite, Tazarotenic acid, with selective affinity for retinoic acid receptors RAR?and RAR. Antiacne; antipsoriatic. Used in treatment of photodamaged skin

Uses

Tazarotene is a prescription topical retinoid sold as a cream or gel. This medication is approved for treatment of psoriasis, acne, and sun damaged skin (photodamage). It is commonly sold in two concentrations: 0.05% and 0.1%. In addition to tretinoin, wh

Uses

anticholelithic

Definition

ChEBI: The ethyl ester of tazarotenic acid. A prodrug for tazarotenic acid, it is used for the treatment of psoriasis, acne, and sun-damaged skin.

Indications

Like other retinoids, tazarotene (Tazorac) acts by binding to RARs and altering gene expression. Tazarotene appears to be particularly selective for the retinoid receptors RAR-β and RAR-γ, but the clinical significance of this observation is unknown.

Manufacturing Process

A mixture of 14.91 g (135.324 mmol) of thiophenol and 5.5 g (137.5 mmol) of NaOH in 100 ml acetone was heated at reflux for 2.5 h and then treated dropwise with a solution of 20 g (134.19 mmol) of 1-bromo-3-methyl-2- butene in 20 ml acetone. This solution was refluxed for 40 h and then stirred at room temperature for 24 h. Solvent was then removed in vacuo, the residue taken up in water, and extracted with 3 times 50 ml ether. Ether extracts were combined and washed with 3 times 30 ml of 5% NaOH solution, then water, saturated NaCl solution and dried. Solvent was then removed in vacuo and the residue further purified by kugelrohr distillation (80°C, 0.75 mm) to give the phenyl-3-methylbut-2-enylsulfide as a pale yellow oil.
To a solution of 15.48 g (86.824 mmol) of phenyl-3-methylbut-2-enylsulfide in 160 ml benzene were added successively 12.6 g (88.767 mmol) of phosphorus pentoxide and 11 ml of 85% phosphoric acid. This solution was refluxed with vigorous stirring under argon for 20 h, then cooled to room temperature. The supernatant organic layer was decanted and the syrupy residue extracted with 3 times 50 ml ether. Organic fractions were combined and washed with water, saturated NaHCO3 and saturated NaCl solution and then dried. Solvent was removed in vacuo and the residue purified by kugelrohr distillation (80°C, 0.5 mm) to give the 4,4-dimethylthiochroman as a pale yellow oil.
A solution of 14.3 g (80.21 mmol) of 4,4-dimethyl thiochroman and 6.76 g (86.12 mmol) of acetyl chloride in 65 ml benzene was cooled in an ice bath and treated dropwise with 26.712 g (102.54 mmol) of stannic chloride. The mixture was stirred at room temperature for 12 h, then treated with 65 ml water and 33 ml conc. hydrogen chloride and heated at reflux for 0.5 h. After being cooled to room temperature, the organic layer was separated and the aqueous layer extracted with 5 times 50 ml benzene. The recovered organic fractions were combined and washed with 5% sodium carbonate solution, water, saturated NaCl solution and then dried. The solvent was removed in vacuo and the residue purified by flash chromatography (silica; 5% ethyl acetate in hexanes) followed by kugelrohr distillation (150°C, 0.7 mm) to give the 4,4-dimethyl-6-acetylthiochroman as a pale yellow oil.
To a solution of 1.441 g (14.2405 mmol) of diisopropylamine in 30 ml dry tetrahydrofuran under argon at -78°C was added dropwise 9 ml of 1.6 M (14.4 mmol) n-butyl lithium in hexane. After stirring this solution at -78°C for 1 h, it was treated dropwise with a solution of 2.95 g (13.389 mmol) of 4,4- dimethyl-6-acetylthiochroman in 5 ml of dry tetrahydrofuran. After another hour of stirring at -78°C, the solution was treated with 2.507 g (14.53 mmol) of diethyl chlorophosphate and brought to room temperature, where it was stirred for 3.75 h. This solution was then transferred using a double ended needle to a solution of lithium diisopropylamide (prepared as above using 2.882 g (28.481 mmol) of diisopropylamine and 18 ml of 1.6 M (28.8 mmol) n-butyl lithium in hexane) in 60 ml dry tetrahydrofuran at -78°C. The cooling bath was removed and the solution stirred at room temperature for 15 h, then quenched with water and acidified to pH 1 with 3 N hydrogen chloride. The mixture was stirred at room temperature for 12 h, then treated with 65 ml water and 33 ml conc. hydrogen chloride and heated at reflux for 0.5 h. After being cooled to room temperature, the organic layer was separated and the aqueous layer extracted with 5 times 50 ml benzene. The recovered organic fractions were combined and washed with 5% sodium carbonate solution, water, saturated NaCl solution and then dried. The solvent was removed in vacuo and the residue purified by flash chromatography (silica; 5% ethyl acetate in hexanes) followed by kugelrohr distillation (150°C, 0.7 mm) to give the 4,4-dimethyl-6-ethynylthiochroman as a pale yellow oil.
A mixture of 15.75 g (0.1 mol) 6-chloronicotinic acid, 6.9 g (0.15 mol) ethanol, 22.7 g (0.11 mol) dicyclohexylcarbodiimide and 3.7 g dimethylaminopyridine in 200 ml methylene chloride was heated at reflux for 2 h. The mixture was allowed to cool, solvent removed in vacuo and residue subjected to flash chromatography to give the ethyl 6-chloronicotinate as a low-melting white solid.
2 Methods of preparation of the ethyl 6-[2-(4,4-dimethylthiochroman-6- yl)ethynyl]nicotinate.
1. Reaction vessels used in this procedure were flame dried under vacuum and all operations carried out in an oxygen-free, argon or nitrogen atmosphere. To a solution of 465.7 mg (2.3019 mmol) of 4,4-dimethyl-6- ethynyl-thiochroman in 4 ml of dry tetrahydrofuran at 0°C was added dropwise 1.5 ml of 1.6 M (2.4 mmol) n-butyl lithium in hexane. This was stirred at 0°C for 10 min and at room temperature for 10 min, cooled again to 0°C and then treated with a solution of 330 mg (2.4215 mmol) of fused ZnCl2 in 4 ml dry tetrahydrofuran using a double ended needle. Thereafter the solution was stirred at 0°C for 30 min, then at room temperature for 10 min. A solution of 426.3 mg (2.2967 mmol) of ethyl 6-chloronicotinoate in 4 ml dry tetrahydrofuran was transferred by double ended needle into a suspension of 430 mg (0.37 mmol) of tetrakistriphenylphosphine palladium in 4 ml dry tetrahydrofuran and stirred at room temperature for 10 min, then treated by double ended needle with the solution of the alkynylzinc prepared above. This mixture was stirred at room temperature for 18 h, then quenched with 100 ml water. Product was recovered by extraction with 3 times 75 ml ether. Ether fractions were combined and washed with saturated NaCl solutions and dried. Solvent was removed in vacuo and the residue purified by flash chromatography (silica; 5% ethyl acetate in hexane) followed by HPLC (Whatman Partisil M-9 10/50; 4% ethyl acetate in hexane) to give the ethyl 6-[2-(4,4-dimethylthiochroman-6-yl)ethynyl]nicotinate.
2. A solution of 15.4 g (76.2 mmol) of 4,4-dimethyl-6-ethynylthiochroman and 14.0 g (75.5 mmol) of ethyl-6-chloronicotinate in 35 ml of freshly distilled triethylamine was degassed and then treated under nitrogen with a finely powdered mixture of 1 g (5.25 mmol) of high purity cuprous iodide and 2 g (2.85 mmol) of bis(triphenylphosphine) palladium (II) chloride. The mixture was heated under nitrogen at 55°C for 20 h and then cooled to room temperature. The triethylamine was then removed under vacuum and the residue was diluted with 200 ml of a 1:4 mixture of ethyl acetate and hexanes. This mixture was filtered through silica and the filtrate concentrated in vacuo. The resultant residue was purified by flash chromatography (silica gel; 15% ethyl acetate in hexanes) and recrystallized from a mixture of ethyl acetate and hexanes to give the ethyl 6-[2-(4,4-dimethylthiochroman-6- yl)ethynyl]nicotinate as a pale yellow solid.

brand name

Avage (Allergan); Tazorac (Allergan).

Therapeutic Function

Keratolytic

Biochem/physiol Actions

Tazarotene induces the expression of tazarotene-induced gene 3 (TIG3), a tumor suppressor gene. It is a prodrug of tazarotenic acid, which specifically activates RARb and RARg, only weakly activates RARa, and is inactive at retinoid X receptors (RXRs). In psoriasis, tazarotene normalizes abnormal keratinocyte differentiation and reduces their hyperproliferation.

Clinical Use

In the United States, tazarotene has been approved for topical treatment of psoriasis (involving up to 20% body surface area) and mild to moderate facial acne. Application site burning, stinging, and desquamation are common side effects, especially with acne. Tazarotene is contraindicated in women who are pregnant.

Side effects

Tazorac is a category X drug and must be avoided in pregnancy. This drug can be irritating and should be avoided in patients with sensitive skin or seborrheic dermatitis.

Structure and conformation

Retinoid prodrug, converted to active form, the carboxylic acid of tazarotene by rapid de-esterification. This drug binds to all three retinoic acid receptors with some increased affinity for the β and γ receptors.