Description
Adapalene is a synthetic retinoid and an agonist of retinoic acid receptors (RARs; K
ds = 1,100, 34, and 130 nM for RARα, RARβ, and RARγ, respectively).
1,2,3,4,5 It inhibits growth and differentiation of sebocytes in a concentration-dependent manner in primary rat preputial cell culture. Adapalene (10 μM) completely inhibits the activity of soybean 15-lipoxygenase (15-LOX) in an enzyme assay and inhibits the 5- and 15-LOX pathways in human blood polymorphonuclear leukocytes (PMNs).
2 It reduces the protein levels of toll-like receptor 2 (TLR2) and IL-10 in skin explants isolated from patients with acne and healthy controls in a concentration-dependent manner but increases the expression of the antigen-presenting protein CD1d in acne skin explants while decreasing it in control explants.
3 It inhibits inflammation in rodent models of ear edema induced by arachidonic acid and carrageenan-induced paw edema.
2 Adapalene (100 μM) also induces apoptosis and inhibits proliferation of CC-531, HT-29, and LoVo colon cancer cells and reduces tumor growth in a DLD-1 colon cancer nude mouse xenograft model in a dose-dependent manner.
5,4 Formulations containing adapalene have been used in the treatment of acne vulgaris.
Chemical Properties
White Crystalline Solid
Originator
Adaferin ,Laboratoires Galderma ,France
Definition
ChEBI: A naphthoic acid that is CD437 in which the phenolic hydroxy group has been converted to its methyl ether.
Indications
Adapalene (Differin) is a polyaromatic retinoidlike
compound that binds to specific retinoic acid nuclear receptors
and is thought to normalize the differentiation
of keratinocytes in the sebaceous acroinfundibulum.
Adapelene is indicated for topical treatment of acne.
Minor local irritation is a common, usually tolerable
side effect. In contrast to other drugs of the retinoid
group, adapalene has not been shown to be teratogenic
in rodents. However, since adequate human studies are
lacking, its use in pregnant women should be discouraged
until further information is available.
Manufacturing Process
Preparation of 6-(3-(1-adamantyl)-4-methoxyphenyl)-2-naphthoic acid consist
of 4 steps.
1. 2-(1-Adamantyl)-4-bromophenol.
34.6 g (200 mmol) of p-bromophenol and 30.4 g (200 mmol) of 1-
adamantanol are dissolved in 100 ml of dichloromethane. To the resulting
solution there are slowly added 10 ml of concentrated sulfuric acid. The
mixture is stirred for 8 hours at ambient temperature, poured into water,
neutralized with sodium bicarbonate, extracted with methylehe chloride, dried
and evaporated. After recrystallization in isooctane 52.8 g of the expected
product are obtained. Yield - 86%. MP: 140°-141°C.
2. 2-(1-Adamantyl)-4-bromoanisole.
To suspension of sodium hydride (80% in oil, 4.32 g, 144 mmol) in 50 ml of
THF, there are slowly added while maintaining the temperature at 20°C, 36.8
g (120 mmol) of 2-(1-adamantyl)-4-bromophenol. The mixture is stirred for 1
hour at ambient temperature at which point 9 ml of methyl iodide are added.
The mixture is then stirred for 2 hours at 20°C, poured into water, extracted
with ether, dried and evaporated. The product is purified by passage through a
silica column (10x30), eluting with a mixture of hexane (90%) and
dichloromethane (10%). On evaporation, 26.2 g of a white solid are obtained.
Yield - 68%. MP: 138°-139°C.
3. Methyl ester of 6-(3-(1-adamantyl)-4-methoxyphenyl)-2-naphthoic acid.
To a suspension of magnesium (1.64 g, 67.5 mmol in 30 ml of THF, there is
added a solution of 1.4 g (4.5 mmol) of 2-(1-adamantyl)-4-bromoanisole and
0.39 ml of dibromoethane in 10 ml of THF. The mixture is stirred until the
reaction is initiated and then there is slowly added a solution of (40.8 mmol)
of 2-(1-adamantyl)-4-bromoanisole in 90 ml of THF. The mixture is refluxed
for 2 hours, and then cooled to 20°C. After that 6.2 g (45 mmol) of
anhydrous ZnCl2 are added. The mixture is stirred for 1 hour at 20°C at which
point 7.95 g (30 mmol) of methyl 6-bromo-2-naphthoate are added followed
by addition of 300 g of NiCl2/1,2-(diphenylphosphino)ethane-complex as the
catalyst. The mixture is stirred again for 2 hours at 20°C, poured into water,
extracted with CH2Cl2 dried and evaporated. The product is isolated by column chromatography, eluting with a mixture of heptane (70%) and
dichloromethane (30%) and then recrystallized in ethyl acetate. 12.2 g of the
expected product are obtained. Yield - 78%. MP: 222°-223°C.
4. 6-(3-(1-Adamantyl)-4-methoxyphenyl)-2-naphthoic acid.
10.5 g of the ester obtained above (step 3) are treated with a solution of soda
in methanol (200 ml, 4.2 N). The mixture is heated at reflux for 48 hours. The
solvents are evaporated and the resulting residue is taken up in water and
acidified with concentrated HCl. The solid is filtered and dried under vacuum
over phosphoric anhydride. The resulting white solid is recrystallized in a
mixture of THF and ethyl acetate. 8.2 g of expected product are obtained.
Yield - 81%. MP: 325°-327°C.
Brand name
Differin (Galderma).
Therapeutic Function
Antiacne
General Description
Adapalene is a third-generation synthetic retinoid and a highly lipophilic compound derived from naphthoic acid. It is widely used in the treatment of acne.
Biological Activity
Retinoic acid analog that is a RAR β and RAR γ agonist (AC 50 values are 2.2, 9.3, 22 and > 1000 nM for RAR β , RAR γ , RAR α and RXR α receptors respectively). Inhibits proliferation and induces apoptosis in colorectal cancer cell in vitro . Displays comedolytic activity.
Biochem/physiol Actions
Retinoic acid analogue that is a RARβ and RARγ agonist (AC50 values are 2.2, 9.3, 22 and > 1000 nM for RARβ, RARγ, RARα and RXRα receptors respectively). Inhibits proliferation and induces apoptosis in colorectal cancer cells in vitro. Displays comedolytic activity. Its unique pharmacological properties make it superior to other retinoids for the treatment of acne.
Structure and conformation
Retinoid-like compound that binds to retinoic acid nuclear receptors,
but not to cytoplasmic receptor proteins.
References
1) Michel et al. (1998), Pharmacology of Adapalene; Br. J. Dermatol., 139 Suppl. 52 3
2) Ocker et al. (2003), The synthetic retinoid adapalene inhibits proliferation and induces apoptosis in colorectal cancer cells on vitro; Int. J. Cancer, 107 453
3) Milikan et al. (2000), Adapalene: an update on newer comparative studies between the various retinoids; Int. J. Dermatol., 39 784
4) Bernard et al. (1993), Adapalene, a new chemical entity with retinoid activity; Skin Pharmacol., 6 61
