Thursday, March 31, 2016

Efinaconazole | Treatment of Onychomycosis | Treatment for Fungal Infection of Nail | 14-Demethylase Inhibitor

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].
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.

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
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

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 199341(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:


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).


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].

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.