5-adamantan-1-yl-n-(2-4-dihydroxybenzyl)-2-4-dimethoxybenzamide and Hyperpigmentation

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.. 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.. 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.. A formulation containing a novel skin whitening ingredient, AP736, effectively reduced pigmentation and was well tolerated by study subjects in summer season.

Topics: Adamantane; Administration, Cutaneous; Adult; Benzamides; Dermatologic Agents; Double-Blind Method; Facial Dermatoses; Female; Humans; Hyperpigmentation; Middle Aged; Seasons; Sunscreening Agents; Young Adult

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.

Topics: Adamantane; Animals; Benzamides; Cell Line, Tumor; Cyclic AMP; Cyclic AMP Response Element-Binding Protein; Cyclic AMP-Dependent Protein Kinases; Gene Expression Regulation; Humans; Hyperpigmentation; Melanins; Melanocytes; Melanoma, Experimental; Mice; Microphthalmia-Associated Transcription Factor; Monophenol Monooxygenase; Signal Transduction; Skin; Skin Neoplasms