Synthesis and Antifungal Activities of (2R,3R)-2-Aryl-1-azolyl-3-(substituted amino)-2-butanol Derivatives as Topical Antifungal Agents.

Ogura, Hironobu; Kobayashi, Haruhito; Nagai, Kiyoshi; Nishida, Tokiko; Naito, Toshiki; Tatsumi, Yoshiyuki; Yokoo, Mamoru; Arika, Tadashi

doi:10.1248/cpb.47.1417

Cited by 31 publications

(21 citation statements)

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“…This discrepancy may be explained by the difference in virulence of the fungal strains used for the trials. Because T. mentagrophytes KD-04 used in this study has the ability to invade the hair follicles (4,9), the prophylactic effect of KP-103 also may be due to its better penetration into the hair follicles than that of the imidazoles.…”

Section: Discussionmentioning

confidence: 99%

KP‐103, a Novel Triazole Derivative, Is Effective in Preventing Relapse and Successfully Treating Experimental Interdigital Tinea Pedis and Tinea Corporis in Guinea Pigs

Tatsumi

Yokoo

Arika

et al. 2002

Microbiology and Immunology

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The therapeutic efficacy of KP‐103, a triazole derivative, for 10 guinea pigs with interdigital tinea pedis or tinea corporis was investigated. Topical KP‐103 solution (0.25 to 1%) was dose‐dependently effective in treating both dermatophytoses. A 1% KP‐103‐treatment rendered all infected skins culture‐negative on day‐2 posttreatment. A high negative‐culture rate was obtained with 1% solutions of butenafine and lanoconazole but not with 1% neticonazole solution. The follow up study performed on day‐30 and day‐9 posttreatment demonstrated that the relapse rates for 1% KP‐103‐treated animals with tinea pedis and for those with tinea corporis were 20 and 30%, respectively, and that these values were the same as those for 1% butenafine‐treated animals, but lower than those for 1% lanoconazole‐treated animals (55 and 80%, respectively). When a single dose of 1% KP‐103 was applied to the back skin 48 hr before fungal inoculation, 9 of the 10 animals were protected from the dermatophytosis, suggesting that active KP‐103 is retained in skin tissue for at least 48 hr after dosing. Moreover, it was suggested that KP‐103 retains a high activity in the horny layer because of its lower keratin‐affinity. The effectiveness of KP‐103 against dermatophytoses may be due to the favorable pharmacokinetic properties in the skin tissues, together with its potent antifungal activity.

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Section: Discussionmentioning

confidence: 99%

KP‐103, a Novel Triazole Derivative, Is Effective in Preventing Relapse and Successfully Treating Experimental Interdigital Tinea Pedis and Tinea Corporis in Guinea Pigs

Tatsumi

Yokoo

Arika

et al. 2002

Microbiology and Immunology

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“…1) is a new triazole antifungal agent developed as a low-surface-tension 10% (wt/wt) topical solution for the treatment of mild to moderate DLSO. It was originally identified as a potent antifungal with in vitro activity minimally affected by keratin (13). The methylene-piperidine group at the C-4 position of the efinaconazole molecule may be responsible for its relatively low keratin binding.…”

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confidence: 99%

The Low Keratin Affinity of Efinaconazole Contributes to Its Nail Penetration and Fungicidal Activity in Topical Onychomycosis Treatment

Sugiura

Sugimoto

Hosaka

et al. 2014

Antimicrob Agents Chemother

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Onychomycosis is a common fungal nail disease that is difficult to treat topically due to the deep location of the infection under the densely keratinized nail plate. Keratin affinity of topical drugs is an important physicochemical property impacting therapeutic efficacy. To be effective, topical drugs must penetrate the nail bed and retain their antifungal activity within the nail matrix, both of which are adversely affected by keratin binding. We investigated these properties for efinaconazole, a new topical antifungal for onychomycosis, compared with those of the existing topical drugs ciclopirox and amorolfine. The efinaconazole free-drug concentration in keratin suspensions was 14.3%, significantly higher than the concentrations of ciclopirox and amorolfine, which were 0.7% and 1.9%, respectively (P < 0.001). Efinaconazole was released from keratin at a higher proportion than in the reference drugs, with about half of the remaining keratin-bound efinaconazole removed after washing. In single-dose in vitro studies, efinaconazole penetrated full-thickness human nails into the receptor phase and also inhibited the growth of Trichophyton rubrum under the nail. In the presence of keratin, efinaconazole exhibited fungicidal activity against Trichophyton mentagrophytes comparable to that of amorolfine and superior to that of ciclopirox. In a guinea pig onychomycosis model with T. mentagrophytes infection, an efinaconazole solution significantly decreased nail fungal burden compared to that of ciclopirox and amorolfine lacquers (P < 0.01). These results suggest that the high nail permeability of efinaconazole and its potent fungicidal activity in the presence of keratin are related to its low keratin affinity, which may contribute to its efficacy in onychomycosis.

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“…We reported that KP-103, a novel topical triazole antimycotic, is highly effective in treating and preventing relapse in guinea pig models of tinea pedis and tinea corporis (16,(24)(25)(26), and its effectiveness is presumably because KP-103 has lower keratin affinity than the existing antifungal drugs and is largely retained as an active form that is not bound to keratin in the horny layer (25).…”

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Therapeutic Efficacy of Topically Applied KP-103 against Experimental Tinea Unguium in Guinea Pigs in Comparison with Amorolfine and Terbinafine

Tatsumi

Yokoo

Senda

et al. 2002

Antimicrob Agents Chemother

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The therapeutic efficacy of KP-103, a novel topical triazole, in a guinea pig tinea unguium model was investigated. Experimental tinea unguium and tinea pedis were produced by inoculation of Trichophyton mentagrophytes SM-110 between the toes of the hind paw of guinea pigs. One percent solution (0.1 ml) of KP-103, amorolfine, or terbinafine was topically applied to the nails and whole sole of an infected foot once daily for 30 consecutive days, and terbinafine was also orally administered at a daily dose of 40 mg/kg of body weight for 30 consecutive days, starting on day 60 postinfection. The fungal burdens of nails and plantar skin were assessed using a new method, which makes it possible to recover infecting fungi by removing a carryover of the drug remaining in the treated tissues into the culture medium. Topically applied KP-103 inhibited the development of nail collapse, significantly reduced the fungal burden of the nails, and sterilized the infected plantar skin. On the other hand, topical amorolfine and topical or oral terbinafine were ineffective for tinea unguium, although these drugs eradicated or reduced the fungal burden of plantar skin. The in vitro activities of amorolfine and terbinafine against T. mentagrophytes SM-110 were 8-and 32-fold, respectively, decreased by the addition of 5% keratin to Sabouraud dextrose broth medium. In contrast, the activity of KP-103 was not affected by keratin because its keratin affinity is lower than those of the reference drugs, suggesting that KP-103 largely exists in the nails as an active form that was not bound to keratin and diffuses in the nail without being trapped by keratin. The effectiveness of KP-103 against tinea unguium is probably due to its favorable pharmacokinetic properties in the nails together with its potent antifungal activity.

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Synthesis and Antifungal Activities of (2R,3R)-2-Aryl-1-azolyl-3-(substituted amino)-2-butanol Derivatives as Topical Antifungal Agents.

Cited by 31 publications

References 0 publications

KP‐103, a Novel Triazole Derivative, Is Effective in Preventing Relapse and Successfully Treating Experimental Interdigital Tinea Pedis and Tinea Corporis in Guinea Pigs

KP‐103, a Novel Triazole Derivative, Is Effective in Preventing Relapse and Successfully Treating Experimental Interdigital Tinea Pedis and Tinea Corporis in Guinea Pigs

The Low Keratin Affinity of Efinaconazole Contributes to Its Nail Penetration and Fungicidal Activity in Topical Onychomycosis Treatment

Therapeutic Efficacy of Topically Applied KP-103 against Experimental Tinea Unguium in Guinea Pigs in Comparison with Amorolfine and Terbinafine

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