In Vitro Human Onychopharmacokinetic and Pharmacodynamic Analyses of ME1111, a New Topical Agent for Onychomycosis

Abstract

ME1111 is a novel antifungal agent currently under clinical development as a topical onychomycosis treatment. A major challenge in the application of topical onychomycotics is penetration and dissemination of antifungal agent into the infected nail plate and bed. In this study, pharmacokinetic/pharmacodynamic parameters of ME1111 that potentially correlate with clinical efficacy were compared with those of marketed topical onychomycosis antifungal agents: efinaconazole, tavaborole, ciclopirox, and amorolfine. An ME1111 solution and other launched topical formulations were applied to an dose model for 14 days based on their clinical dose and administration. Drug concentrations in the deep layer of the nail and within the cotton pads beneath the nails were measured using liquid chromatography-tandem mass spectrometry. Concentrations of ME1111 in the nail and cotton pads were much higher than those of efinaconazole, ciclopirox, and amorolfine. Free drug concentrations of ME1111 in deep nail layers and cotton pads were orders of magnitude higher than the MIC value against ( = 30). Unlike other drugs, the antifungal activity of ME1111 was not affected by 5% human keratin and under a mild acidic condition (pH 5.0). The antidermatophytic efficacy coefficients (ratio of free drug concentration to MICs against ) of ME1111, as measured in deep nail layers, were significantly higher than those of efinaconazole, tavaborole, ciclopirox, and amorolfine ( < 0.05). This suggests that ME1111 has excellent permeation of human nails and, consequently, the potential to be an effective topical onychomycosis treatment.

Synthesis and Influence of 3-Amino Benzoxaboroles Structure on Their Activity against Candida albicans

“…However, in the case of 14 the insertion of the formyl substituent in the ortho position relative to the boronic moiety causes the significant O1-B1-O2 angle narrowing (from 123.1(1) in 11 to 118.4(2)° in 14) with simultaneous O1-B1-C1 angle broadening (from 128.3(1) in 11 to 133.5(2)° in 14), whereas the five-membered ring inner O2-B1-C1 angle is retained. This is following the findings by Czerwińska et al [29] associating the strains in the boron coordination sphere with the position of the hydrogen atom in syn (11) or anti position (14). In the latter such a conformation may be imposed by the presence of a relatively strong intramolecular O1-H…O3 hydrogen bond (H…O and O…O distances equal 2.15(2) and 2.867(2) Å , respectively; O-H…O angle equals 147(2)°), leading to a formation of a six-membered H-bonded ring, essentially flat and coplanar with the benzoxaborole unit (deviation from a plane defined by all atoms except the phenylpiperazine substituent is only 0.019(2) Å ).…”

“…Yield: 1.85 g; 8 mmol; 79%. 1 3-(4-Phenylpiperazin-1-yl)-2,1-benzoxaborol-1(3H)-ol (11) A solution of (2-formylphenyl)boronic acid (1.5 g; 10 mmol) in diethyl ether (70 mL) was stirred in a 100 mL flask at room temperature. Next, 1-phenylpiperazine (1.6 g; 1.5 mL; 10 mmol) was added during 5 min resulting immediately in precipitation of a white solid.…”

“…Despite Candida is the leading reason of the opportunistic mycoses, there is a limited number of antifungal agents available for the therapy [5]. Tavaborole (AN2690, Figure 1) is a small-molecule approved by the American Food and Drug Administration (FDA) in 2014 for the treatment of onychomycosis caused by dermatophyte fungi [6][7][8][9][10][11][12]. A relatively low molecular weight of Tavaborole results in high penetration into the nailplate [13].…”

“…Tavaborole (AN2690, Figure 1 ) is a small-molecule approved by the American Food and Drug Administration (FDA) in 2014 for the treatment of onychomycosis caused by dermatophyte fungi [ 6 , 7 , 8 , 9 , 10 , 11 , 12 ].…”

“…Structures of unsubstituted benzoxaborole (6) and its studied derivatives(7)(8)(9)(10)(11)(12)(13)(14)(15).…”