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Background/purpose: AP736 is a novel compound with an adamantyl benzylbenzamide moiety that has shown antimelanogenic activity in melanocytes in vitro and in artificial skin equivalent through the inhibition of key melanogenic enzymes and suppression of the cAMP-phosphokinase A-cAMP response element-binding protein signaling pathway. To estimate the clinical effectiveness of AP736 for the treatment of facial hyperpigmentation, we examined the efficacy and safety of a topical formulation containing AP736 compared with a vehicle formulation in human facial skin. To evaluate the degree of whitening when used in a real-life situation, subjects with hyperpigmentation conditions were selected and the trial was performed from mid-May to the end of June, when there are strong UV rays in Korea., Materials and Methods: Forty-eight healthy Korean women aged 20-60 years were enrolled in this study for 6 weeks. Women who were pregnant or undergoing any concurrent therapy were excluded. Subjects were instructed to apply a randomly assigned formulation containing 0.5% AP736 (test formulation; n = 24) or vehicle (vehicle control; n = 24) in addition to an assigned sunscreen with a twice-daily application protocol. The degree of facial pigmentation was measured objectively using a Mexameter MX18 and Chromameter CM700, in addition to assessment by physicians using clinical photographs., Results: The AP736 formulation was significantly (P < 0.05) more effective than the vehicle control formation in reducing the appearance of pigmentation at 3- and 6-week follow-up visits., Conclusion: A formulation containing a novel skin whitening ingredient, AP736, effectively reduced pigmentation and was well tolerated by study subjects in summer season., (© 2015 The International Society of Dermatology.)

Numerous medications are used to treat hyperpigmentation. However, several reports have indicated that repeated application of some agents, such as rhododendrol (RD), raspberry ketone (RK) and monobenzone (MB), can be toxic to melanocytes. Although these agents had severe side effects in human trials, no current in vitro methods can predict the safety of such drugs. This study assessed the in vitro effects of five depigmentary compounds including leukoderma-inducing agents. In particular, we determined the effects of different concentrations and exposure times of different depigmentary agents on cell viability and melanogenesis in the presence and absence of ultraviolet B (UVB) radiation. Concentrations of RD, RK and MB that inhibit melanogenesis are similar to concentrations that are cytotoxic; however, concentrations of rucinol (RC) and AP736 that inhibit melanogenesis are much lower than concentrations that are cytotoxic. Furthermore, the concentrations that cause toxic effects depend on exposure duration, and prolonged exposure to RD, RK and MB had more cytotoxic effects than prolonged exposure to RC and AP736. The cytotoxic effects of RD and RK appear to be mediated by apoptosis due to increased expression of caspase-3 and caspase-8; UVB radiation increased the cytotoxicity of these agents and also increased caspase activity. Our results indicate that different leukoderma-inducing compounds have different effects on the viability of normal epidermal melanocytes and suggest that the in vitro assay used here can be used to predict whether an investigational compound that induces leukoderma may lead to adverse effects in human trials., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Three-dimensional quantitative structure-activity relationship (3D-QSAR) modeling, comparative molecular field analysis (CoMFA), and comparative molecular similarity indices analysis (CoMSIA) of polyhydroxylated N-benzylbenzamide derivatives containing an adamantyl moiety were performed to understand the mechanism of action and structure-activity relationship of these compounds. Contour map analysis indicated that steric contributions of the adamantyl moiety and electrostatic contributions of the hydroxyl group at the 3-position are important in the activity. Activities of the training set and test sets predicted by CoMFA fit well with actual activities, demonstrating that CoMFA, along with the best calculated q(2) value, has the best predictive ability., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Melanogenesis is essential for the protection of skin against UV, but excessive production of melanin causes unaesthetic hyperpigmentation. Much effort is being made to develop effective depigmenting agents. Here, we found that a tyrosinase inhibitor, AP736 (5-adamantan-1-yl-N-(2,4-dihydroxy-benzyl)-2,4-dimethoxy-benzamide) potently suppresses tyrosinase expression, and the mechanism underlying was elucidated. AP736 attenuated the melanin production induced by diverse melanogenic stimuli in murine and human melanocytes. It suppressed the expression of key melanogenic enzymes; tyrosinase, tyrosinase-related protein-1 and tyrosinase-related protein-2. The expression of microphthalmia-associated transcription factor (MiTF), a major promoter of melanogenesis was also decreased. AP736 inhibited the activation of cAMP response element-binding protein (CREB) and phosphokinase A (PKA), and cAMP elevation, reflecting that cAMP-PKA-CREB signalling axis was suppressed, resulting in the downregulation of MiTF and tyrosinase. Along with the previously reported tyrosinase inhibitory activity, the suppression of cAMP-PKA-CREB-mediated MiTF and tyrosinase expression by AP736 may be efficient for the treatment for hyperpigmentation., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

A new series of polyhydroxylated N-benzylbenzamide derivatives containing an adamantyl moiety has been synthesized, and the depigmenting and tyrosinase inhibitory activities of the molecules were evaluated. The lipophilic character of the adamantyl moiety appeared to confer greater depigmentation power on the benzamide derivatives as compared to those lacking adamantyl substitution. Molecular modeling was applied in order to elucidate the interactions between ligands and tyrosinase that led to inhibition., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Six diphenolic compounds containing adamantane moiety were synthesized and evaluated as potent inhibitors on tyrosinase activity and melanin formation in Melan-A cells. The inhibitory activity of 4-adamantyl resorcinol 1 was similar to that of 4-n-butyl resorcinol in both assays. However, dihydroxyl benzamide derivatives 6a-e showed different inhibitory patterns. All derivatives significantly suppressed the cellular melanin formation without tyrosinase inhibitory activities. These behaviors indicated that the introduction of amide bond changes the binding mode of dihydroxyl groups to tyrosinase. Among derivatives, 6d (3,4-dihydroxyl compound) and 6e (2,3-dihydroxyl compound) showed stronger inhibitory activities (IC(50)=1.25 microM and 0.73 microM, respectively) as compared to 4-n-butyl resorcinol (IC(50)=21.64 microM) and hydroquinone (IC(50)=3.97 microM). This study showed that the position of dihydroxyl substituent at aromatic ring is important for the intercellular inhibition of melanin formation, and also amide linkage and adamantane moiety enhance the inhibition.