Efinaconazole
[(2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-a,2,4-triazol-1-yl)butan-2-ol],
a novel triazole antifungal drug is developed as a topical treatment for
onychomycosis, a fungal infection of nail. It has demonstrated efficacy in
patients with toe nail onychomycosis in two phase 3 clinical trials.
Onychomycosis and other superficial mycoses are caused mainly by dermatophytes
(e.g., Trichophyton rubrum and Trichophyton mentagrophytes) and yeast
(e.g., Candida albicans) [1].
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| Efinaconazole: 2D and 3D Structure |
Efinaconazole
is believed to work by 14-demethylase (14-DM) inhibition, which is a key
pathway in ergosterol synthesis. Inhibition of ergosterol prevents secondary
degenerative changes in the nail bed, plate, and surrounding tissue. Efinaconazole
possesses similar or higher antifungal activity against T. rubrum and T.
mentagrophytes (Minimum Inhibitory Concentration range, 0.00098 to 0.031 ug/ml) and a broader spectrum
of activity than those of currently marketed antifungals used in onychomycosis [1].
What is Ergosteol?
Ergosterol
is an important structural component of fungal cell membranes, maintaining
membrane fluidity and a permeability barrier, and is essential for fungal cell
viability. Several classes of antifungal drugs target ergosterol biosynthesis.
Among these, triazole antifungals (e.g., itraconazole) and imidazole
antifungals (e.g., clotrimazole and miconazole) inhibit sterol 14-demethylase in
the ergosterol biosynthesis pathway. The consequent ergosterol depletion
affects cell membrane integrity and function and is believed to inhibit fungal
cell growth and affect morphology.
Efinaconazole blocks Ergosterol Biosynthesis
Efinaconazole is a triazole antifungal
agent that exerts its antifungal effects by blocking ergosterol biosynthesis,
presumably through sterol 14α-demethylase (14-DMT) inhibition, an enzyme involved
in the conversion of lanosterol to ergosterol. The ensuing ergosterol depletion
and accumulation of precursor sterol are thought to affect cell membrane
integrity and function, leading to secondary degenerative changes [1].
A comprehensive survey of clinical
isolates of T. rubrum, T. mentagrophytes, and C. albicans (common causative
onychomycosis pathogens) showed that efinaconazole had potent and broad
spectrum antifungal activity. Efinaconazole minimum inhibitory concentrations (MICs - assessed using a broth dilution assay) against 1,493 T. rubrum and T.
mentagrophytes isolates ranged from less than 0.002 to 0.06 ug/ml [90% of
isolates were inhibited (MIC90) at 0.008 and 0.015 ug/ml,
respectively] and MICs against 105 C. albicans isolates ranged from less than 0.0005
to greater than 0.25 ug/ml [50% of isolates inhibited (MIC50) by
0.001 and 0.004 ug/ml at 24 and 48 h, respectively] [2, 3].
Efinaconazole was also active against
other fungal pathogens, including Trichophyton,
Microsporum, Epidermophyton, Acremonium, Fusarium, Paecilomyces,
Pseudallescheria, Scopulariopsis, Aspergillus, Cryptococcus, Trichosporon
and Candida species. No apparent
increase in susceptibility was seen in 13 T.
rubrum toe-nail isolates from onychomycosis patients treated daily with
efinaconazole 10% solution for 48 weeks, suggesting a low potential for
dermatophytes to develop resistance to efinaconazole.
Moreover, the antifungal activity of efinaconazole was not affected by keratin because of its lower affinity for keratin relative, suggesting that the drug exists in the nails as an active form unbound to keratin and diffuses in the nail without being trapped by keratin. This activity suggests that the therapeutic efficacy of efinaconazole may be because of good retention of its antifungal activity in skin tissue, in addition to its potency [4].
Dosages
and Approvals:
Efinaconazole (Tradename: Jublia) is indicated for the treatment of mild to
moderate onychomycosis, a common and destructive nail infection caused
predominantly by dermatophyte fungi. Non-lacquer 10 % topical solution of
efinaconazole, was approved by Health Canada for the treatment of onychomycosis
in October 2013. In 2014, the U.S. Food and Drug Administration (FDA) approved
Jublia, as the first topical triazole for the treatment of onychomycosis of the
toenails.
Although oral treatments are generally
considered more effective than topical antifungals, their use is limited by
safety issues and potential drug-drug interactions in under-treatment patients,
especially elderly. Topical treatments, being applied directly onto the
affected area, provide drug exposure at the site of infection and decrease the
risk of systemic exposure; however, the efficacy of these agents is limited by their
nail plate penetration and the ability to maintain a sustained concentration
above the minimum inhibitory concentration (MIC) for the infecting fungus.
In May
2006, Dow Pharmaceutical Sciences licensed rights to Efinaconazole from Kaken
Pharmaceuticals, the originator of the product, in the Americas and the EU. Dow
Pharmaceutical Sciences was acquired by and became a wholly-owned subsidiary of
Valeant Pharmaceuticals International in December 2008.
Summary
Common name: IDP 108; IDP-108;
IDP108; KP 103; KP-103; KP103
Trademarks: Jublia
Molecular Formula: C18H22F2N4O
CAS Registry Number: 164650-44-6
CAS Name: (2R,3R)-2-(2,4-Difluorophenyl)-3-(4-methylene-1-piperidinyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol
Molecular Weight: 348.39
SMILES:C[C@H]([C@](CN1C=NC=N1)(C2=C(C=C(C=C2)F)F)O)N3CCC(=C)CC3
InChI Key: NFEZZTICAUWDHU-RDTXWAMCSA-N
InChI: InChI=1S/C18H22F2N4O/c1-13-5-7-23(8-6-13)14(2)18(25,10-24-12-21-11-22-24)16-4-3-15(19)9-17(16)20/h3-4,9,11-12,14,25H,1,5-8,10H2,2H3/t14-,18-/m1/s1
Mechanism of Action: 14α-Demethylase
(14-DMT) Inhibitor
Activity: Treatment of Onychomycosis; Treatment
of Fungal Nail Infection; Topical Dermatological Antifungals
Status: Launched 2014 (US); 2013 (Canada)
Chemical Class: Piperidines; Small-molecules;
Triazoles; Flourine containing; Hydroxyl containing
Originator: Valeant Pharmaceuticals
Chem Pharm Bull 1999, 47(10), 1417-1425: This article reports first known synthesis for Efinaconazole. It also reports route to prepare various important intermediates for synthesis.
Intermediate 1:
Chem Pharm Bull 1993, 41(6), 1035-1042: The optically active oxirane is reported here. All subsequent works from the group follow the reported procedure.
Intermediate 2:
US20130150586A1: The patent reports optimized route for the final synthesis. It catalogs various yields taking with various combination of piperidine intermediate.
Final Synthesis:
J Org Chem 2014, 79(7), 3272-3278: The article reports an optimized synthesis route to prepare the epoxide intermediate. The authors then prepared Efinaconazole via microwave synthesis. The yield was an impressive 90%. Synthesis following the aldehyde are reported as one-pot process.
Microwave Synthesis:
Efinaconazole Synthesis
Chem Pharm Bull 1999, 47(10), 1417-1425: This article reports first known synthesis for Efinaconazole. It also reports route to prepare various important intermediates for synthesis.
Intermediate 1:
Chem Pharm Bull 1993, 41(6), 1035-1042: The optically active oxirane is reported here. All subsequent works from the group follow the reported procedure.
Intermediate 2:
US20130150586A1: The patent reports optimized route for the final synthesis. It catalogs various yields taking with various combination of piperidine intermediate.
Final Synthesis:
J Org Chem 2014, 79(7), 3272-3278: The article reports an optimized synthesis route to prepare the epoxide intermediate. The authors then prepared Efinaconazole via microwave synthesis. The yield was an impressive 90%. Synthesis following the aldehyde are reported as one-pot process.
Microwave Synthesis:
Identifications:
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| 1H NMR Estimated for Efinaconazole |
Experimental: 1H-NMR
(500 MHz, CDCl3) δ: 0.96 (3H, dd,
J=2.68, 7.08 Hz), 2.13-2.26 (4H, m), 2.35 (2H, br), 2.70 (2H, br), 2.90-2.94
(1H, q, J=7.08 Hz), 4.64 (2H, s), 4.82 (1H, dd, J=0.73, 14.39 Hz), 4.87 (1H,
dd, J=0.73, 14.39 Hz), 5.45 (1H, s), 6.72-6.81 (2H, m), 7.51 (1H, dt, J=6.59,
9.03 Hz), 7.78 (1H, s), 8.02 (1H, s).
Sideeffects:
The
most common treatment related adverse events (AEs) in efinaconazole recipients
were nasopharyngitis and upper respiratory tract infection. In rare case conditions
such as skin laceration, arthralgia and back pain (each occurring in one
patient), were reported but none of which were serious or considered treatment
related. Up to 10% of subjects had burning and/or itching, which were not
considered as adverse events, and one patient experienced mild redness on day 7
after application of efinaconazole. All adverse events in patients and healthy
volunteers resolved without use of concomitant therapy [2].
References:
1. Tatsumi, Y.; et. al. Mechanism of action of efinaconazole, a novel triazole antifungal agent. Antimicrob Agents Chemother 2013, 57(5), 2405-2409.2. Patel, T.; et. al. Efinaconazole: first global approval. Drugs 2013, 73(17), 1977-1983.
3. Jo Siu, W. J.; et. al. Comparison of in vitro antifungal activities of efinaconazole and currently available antifungal agents against a variety of pathogenic fungi associated with onychomycosis. Antimicrob Agents Chemother 2013, 57(4), 1610-1616.
4. Tatsumi, Y.; et. al. In vitro antifungal activity of KP-103, a novel triazole derivative, and its therapeutic efficacy against experimental plantar tinea pedis and cutaneous candidiasis in guinea pigs. Antimicrob Agents Chemother 2001, 45(5), 1493-1499.
5. Mimura, M.; et. al. Process for producing 1-triazole-2-butanol derivatives. US20130150586A1
6. Ogura, H.; et. al. Synthesis and Antifungal Activities of (2R,3R)-2-Aryl-1-azolyl-3-(substituted amino)-2-butanol Derivatives as Topical Antifungal Agents. Chem Pharm Bull 1999, 47(10), 1417-1425.
