Description
Nepafenac, launched by Alcon Laboratories, is a topical ophthalmic
medication indicated for the treatment of ocular pain and inflammation associated
with cataract surgery. Nepafenac is a prodrug of amfenac, which is an NSAID and
a potent non-selective inhibitor of COX-1 (IC50=0.25 μM)) and COX-2
(IC50=0.15μM). Nepefenac itself exhibits only weak activity against COX-1
(IC50=64.3μM). Amfenac (Fenazox) has been marketed in Japan since 1986 for
the treatment of rheumatoid arthritis, post-surgical pain, and inflammation. With
most NSAIDs that are currently being used as topical ophthalmic agents, the
maximum drug concentration is achieved on the ocular surface, with progressively
lower concentrations in the cornea, aqueous humor, vitreous, and retina. Nepafenac
has been found to have a penetration coefficient that is 4 – 28 times greater
than that achieved with conventional NSAIDs such as diclofenac, bromofenac, and
ketorolac. In addition, the bioconversion of nepefenac to amfenac is primarily
mediated by ocular tissue hydrolases, specifically in the iris, ciliary body, retina, and
choroid. The enhanced permeability of nepefenac combined with rapid bioactivation
in the ocular tissue translates into superior anti-inflammatory efficacy at the
target sites. In preclinical models, a single topical ocular dose of nepefenac (0.1%)
inhibits prostaglandin synthesis in the iris/ciliary body by 85–95% for more than
6 h, and in the retina/choroid by 55% for up to at least 4 h. By comparison, diclofenac
(0.1%) shows 100% inhibition of prostaglandin synthesis in the iris/ciliary
body for only 20 min, with 75% recovery observed within 6 h. Diclofenac’s inhibition
of prostaglandin synthesis in the retina/choroids is minimal. The recommended
dose of nepafenac ophthalmic suspension is one drop in the affected eye(s)
three times daily beginning one day prior to cataract surgery, continued on the day
of surgery and through the first two weeks of the postoperative period. Although
the drug is applied topically, low but quantifiable plasma concentrations of nepefenac
and amfenac are observed in majority of the subjects following t.i.d. dosing
of nepefenac ophthalmic solution. The clinical significance of the systemic absorption
of nepefenac after ophthalmic administration is unknown. The efficacy of
nepafenac was demonstrated in two placebo-controlled clinical studies involving
over 680 patients. Nepafenac suspension was dosed three times daily, beginning one
day prior to cataract surgery, continuing on the day of surgery, and for 14 days
postoperatively.
Chemical Properties
Light Yellow Solid
Originator
AH Robins (US)
Uses
Labelled Nepafenac (N390080). A non-steroidal anti-inflammatory with analgesic activity; selective COX-2 inhibitor. Prodrug of Amfenac.
Uses
Nepafenac is a non-steroidal anti-inflammatory drug (NSAID), usually sold as a prescription eye drop. It reduces pain and inflammation in the eyes. Nepafenac ophthalmic is used to reduce pain and swelling after cataract surgery. Its side effects may inclu
Definition
ChEBI: A monocarboxylic acid amide that is amfenac in which the carboxylic acid group has been converted to the corresponding carboxamide. It is a prodrug for amfenac, used in eye drops to treat pain and inflammation following cataract surgery.
Brand name
Nevanac (Alcon).
Biochem/physiol Actions
Nepafenac is a NSAID (nonsteroidal anti inflammatory drug) that is routinely used in opthamology to control pain following cataract surgery.
Clinical Use
Nepafenac is a novel ophthalmic non-steroidal anti-inflammatory drug (NSAID), for the treatment of eye pain and inflammation caused by cataract surgery, compared with traditional NSAIDs, chemical structure of Nepafenac is conducive to make it rapidly penetrate the cornea and distribute to its target site, which is helpful to reduce the accumulation of the drug in the corneal surface and to reduce the incidence of complications of the eye surface, it has many advantages such as infiltration, targeting strong, little toxic side effects and so on.
August 19, 2005 ,the US Food and Drug Administration (FDA) approved nepafenac ophthalmic suspension for the treatment of cataract surgery-related pain and inflammation, it is the first ophthalmic NSAID prodrug formulation approved for marketing.
Nepafenac after ocular administration, can rapidly pass through the cornea , and under the action of eye tissue hydrolytic enzymes,it can become into ammonia diclofenac (a kind of NSAID); and ammonia diclofenac by inhibiting prostaglandin H synthase ( cyclooxygenase), can block prostaglandin synthesis to play its role as an anti-inflammatory analgesic. As is known, prostaglandin is one of the media causing ocular inflammation it can lead to blood-aqueous barrier crash, vasodilatation, increased vascular permeability and leukocyte chemotaxis, etc. In addition, prostaglandins can also control contraction of the iris sphincter through non-cholinergic mechanism which can trigger the miosis reaction during eye surgery and after surgery. After ocular administration of NSAIDs, it can inhibit prostaglandins synthesis in the iris, ciliary body and conjunctiva, so people can prevent eye inflammation, and reduce the associated pain.
The above information is edited by the chemicalbook of Tian Ye.
Synthesis
The synthesis of nepafenac started with commercially available 2-amino-benzophenone
(89). Compound 89 was reacted with t-butyl hypochrite at ¨C
65??C in DCM to give a mono-N-chloroaniline (90) which
was subsequently treated with methylthioacetamide in THF
at ¨C65??C in the same pot to give an aza-sulfonium salt 91 as
a solid. Compound 91 was slurred in DCM and triethylamine
was added to give sulfer ylide 92 intermediate which under-went a Sommelet-Hauser type rearrangement to give compound
93 after re-aromatization of the intermediate cyclohexadienone
imine. Compound 93 was finally reduced with
Raney nickel to give nepafenac (XIV) in 73% yield as yellow
needles.
Veterinary Drugs and Treatments
Nepafenac is a nonsteroidal anti-inflammatory and analgesic prodrug.
After topical ocular dosing, nepafenac penetrates the cornea and
is converted by ocular tissue hydrolases to amfenac, a nonsteroidal
anti-inflammatory drug. Amfenac is thought to inhibit the action
of prostaglandin H synthase (cyclooxygenase), an enzyme required
for prostaglandin production. Nepafenac is indicated for the treatment
of pain and inflammation associated with cataract surgery.
Clinical claims and research
In preclinical models, a single topical ocular dose of nepefenac (0.1%) inhibits prostaglandin synthesis in the iris/ciliary body by 85–95% for more than 6 h, and in the retina/choroid by 55% for up to at least 4 h. By comparison, diclofenac (0.1%) shows 100% inhibition of prostaglandin synthesis in the iris/ciliary body for only 20 min, with 75% recovery observed within 6 h. Diclofenac’s inhibition of prostaglandin synthesis in the retina/choroids is minimal. The recommended dose of nepafenac ophthalmic suspension is one drop in the affected eye(s) three times daily beginning one day prior to cataract surgery, continued on the day of surgery and through the first two weeks of the postoperative period. Although the drug is applied topically, low but quantifiable plasma concentrations of nepefenac and amfenac are observed in majority of the subjects following t.i.d. dosing of nepefenac ophthalmic solution. The clinical significance of the systemic absorption of nepefenac after ophthalmic administration is unknown. The efficacy of nepafenac was demonstrated in two placebo-controlled clinical studies involving over 680 patients. Nepafenac suspension was dosed three times daily, beginning one day prior to cataract surgery, continuing on the day of surgery, and for 14 days postoperatively.
Mode of action
Nepafenac is a non-steroidal anti-inflammatory and analgesic prodrug. After topical ocular dosing, nepafenac penetrates the cornea and is converted by ocular tissue hydrolases to amfenac, a nonsteroidal anti-inflammatory drug. Amfenac inhibits the action of prostaglandin H synthase (cyclooxygenase), an enzyme required for prostaglandin production.
References
[1] bucolo c1, marrazzo g, platania cb, romano gl, drago f, salomone s. effects of topical indomethacin, bromfenac and nepafenac on lipopolysaccharide-induced ocular inflammation. j pharm pharmacol. 2014 jul;66(7):954-60.
[2] marshall jc1, caissie al, cruess sr, cools-lartigue j, burnier mn jr. the effects of a cyclooxygenase-2 (cox-2) expression and inhibition on human uveal melanoma cell proliferation and macrophage nitric oxide production. j carcinog. 2007 nov 27;6:17.
