Tavaborole | Treatment of Onychomycosis | Leucyl-tRNA Synthetase Inhibitor

Tavaborole [5-Fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole] is a novel, small molecule oxaborole antifungal developed for the topical treatment of onychomycosis of the toenail. In 2014, the drug received its first global approval for this indication in the US. 

Tavaborole exerts its antifungal activity by blocking cellular protein synthesis via inhibition of yeast cytoplasmic leucyl-aminoacyl transfer RNA (tRNA) synthetase. The inhibition of protein synthesis leads to termination of cell growth and then cell death, eliminating the fungal infection.

Tavaborole: 2D and 3D Structure

In in vitro studies, Tavaborole showed minimal inhibitory concentrations (MICs) of 1-8 ug/mL against the dermatophytes T. mentagrophytes and T. rubrum (the primary causative agents of onychomycosis). Tavaborole was fungicidal against T. rubrum and T. mentagrophytes with minimum fungicidal concentrations (MFC₅₀) of 64 ug/mL [1, 2].

Treatment for Onychomycosis

Subungual onychomycosis is difficult to treat due to the poorly perfused location of the infection. To be effective, a topical treatment must penetrate the nail plate and reach the site of infection at a concentration sufficient to exert antifungal activity.  Tavaborole a novel, low molecular weight (151.9 Da) oxaborole antifungal drug has been shown to penetrate the nail after topical application at concentrations sufficient to inhibit the primary causative fungi of onychomycosis. 

Toenails are more commonly affected than fingernails: onychomycosis in these cases frequently involves several nails, and dry-type plantar tinea pedis is often present [3]. There are different clinical types of onychomycosis, depending on the modality of nail invasion. Clinical diagnosis of onychomycosis always requires laboratory confirmation, and treatment depends on many factors, like the fungus species and the number of affected nails.

Tavaborole exerts its antifungal activity by blocking cellular protein synthesis via inhibition of yeast cytoplasmic leucyl-aminoacyl transfer RNA (tRNA) synthetase. Formation of a stable tRNA^Leu-tavaborole adduct (resulting from the boron atom of the oxaborole ring binding to the 2’, 3’-hydroxy groups on the tRNA 3’-terminal adenosine) inhibits leucyl-tRNA^Leu synthesis, consequentially blocking protein synthesis. Tavaborole analogs where boron was replaced with carbon had no activity, demonstrating the boron atom in the oxaborole ring is essential for the drugs mechanism of fungal inhibition.

Tavaborole against Dermatophytes:

 In in vitro studies, Tavaborole showed minimal inhibitory concentrations (MICs) of 1-8 ug/mL against the dermatophytes T. mentagrophytes and T. rubrum (the primary causative agents of onychomycosis) and of less than 0.5-4 ug/mL against Trichophyton tonsurans, Epidermophyton floccosum, Microsporum audouinii, Microsporum canis and Microsporum gypseum.

Tavaborole was also active against Aspergillus fumigatus, Candida spp., Cryptococcus neoformans, Fusarium solani, Malassezia spp. and Saccharomyces cerevisiae with MIC values of between 0.25 and 1 u/mL. Tavaborole was fungicidal against T. rubrum and T. mentagrophytes with minimum fungicidal concentrations (MFC₅₀) of 64 ug/mL.

The presence of 5 % powdered keratin had no effect on the microbiological activity of the drug against T. rubrum.

Dosages and Approval:

Tavaborole as 5% topical solution (Trademark: Kerydin) has been approved in by the US Food and Drug Administration (FDA) in 2014 for the treatment of onychomycosis of the toenails caused by Trichophyton mentagrophytes or Trichophyton rubrum.

Tavaborole was discovered and developed by Anacor pharmaceuticals. In early 2007 Anacor entered into an exclusive worldwide licensing agreement with Schering-Plough Corporation (now a subsidiary of Merck) for the development and commercialisation of Tavaborole, which led to the two companies successfully manufacturing the product candidate and completing certain phase III development activities. In February 2010, Merck returned full worldwide development and commercialisation rights for the drug to Anacor.

Tavaborole Synthesis

US5880188A: It is one of the oldest reported synthetic procedure.

Tetrahedron 2007, 63, 9401-9405: A convenient one-pot synthesis of Tavaborole has been developed via the reaction of o-bromobenzyl alcohols with NaH, n-BuLi, and B(O-ⁱPr)₃.

J Med Chem 2006, 49(15), 4447-4450: The article reports an industrially viable synthetic procedure. It also reports synthesis for various Tavaborole analogues, along-with activity against various strains.

Identifications:

Experimental: ¹H NMR (300MHz, DMSO-d6) δ (ppm) 4.95 (s, 2H), 7.15 (m, 1H), 7.24 (dd, J = 9.7, 1.8 Hz, 1H), 7.74 (dd, J = 8.2, 6.2 Hz, 1H), 9.22 (s, 1H).

Sideeffects: The most common adverse event (AE) reported was topical irritation; application site reactions were generally mild to moderate in severity and reversible. Adverse events occurring in greater than 5 % of patients regardless of relationship to treatment included influenza, pharyngitis, tinea pedis, upper respiratory tract infection, tooth abscesses, gastroenteritis and peripheral oedema.

References:

1. Markham, A. Tavaborole: First Global Approval. Drugs 2014, 74(13), 1555-1558. (FMO only)

2. Rock, F. L.; et. al. An antifungal agent inhibits an aminoacyl-tRNA synthetase by trapping tRNA in the editing site. Science 2007, 316(5832), 1759-1761. (FMO only)
3. Piraccini, B. M.; et. al. Onychomycosis: A Review. J Fungi 2015, 1(1), 30-43. (free copy)

4. Austin, P. W.; et. al. Oxaboroles and salts thereof, and their use as biocides. US5880188A

5. Gunasekera, D. S.; et. al. Practical synthesis and applications of benzoboroxoles. Tetrahedron 2007, 63, 9401-9405. (FMO only)
6. Baker, S. J.; et. al. Discovery of a New Boron-Containing Antifungal Agent, 5-Fluoro-1,3-dihydro-1-hydroxy-2,1- benzoxaborole (AN2690), for the Potential Treatment of Onychomycosis. J Med Chem 2006, 49(15), 4447-4450. (FMO only)

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.

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

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:

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.