Thiamidol (isobutylamido thiazolyl resorcinol): A Highly Specific Human Tyrosinase Inhibitor for the Treatment of Hyperpigmentation

Thiamidol (isobutylamido thiazolyl resorcinol): A Highly Specific Human Tyrosinase Inhibitor for the Treatment of Hyperpigmentation Tobias Mann1, Wolfram Gerwat1, Jan Batzer1, Kerstin Eggers1, Cathrin Scherner1, Horst Wenck1, Franz Stab1, Vincent J. Hearing2, Klaus-Heinrich Rohm3, Ludger Kolbe1 1Front End Innovation, Beiersdorf AG, Hamburg, Germany; 2DASS Manuscript, Haymarket, Virginia, USA; 3Institute of Physiological Chemistry, Philipps University, Marburg, Germany Tyrosinase is the rate-limiting enzyme of melanin production, and accordingly, is the most prominent target for inhibiting hyperpigmentation. Numerous tyrosinase inhibitors have previously been identified; however, most lack clinical efficacy because they were identified using mushroom tyrosinase as the target substrate. Therefore, we used recombinant human tyrosinase to screen a library of 50,000 compounds and compared the active screening hits with well-known anti-pigmentation ingredients, including 4-butylresorcinol, kojic acid, rhododendrol, hydroquinone, and arbutin. Hydroquinone and its derivative arbutin only weakly inhibited human tyrosinase with a half-maximal inhibitory concentration (IC50) in the millimolar range, and kojic acid showed a weak efficacy (IC50 > 500 mmol/L). The most potent inhibitors of human tyrosinase identified in this screening were resorcinol-thiazole derivatives, specifically the newly identified Thiamidol (Beiersdorf AG, Hamburg, Germany) (isobutylamido thiazolyl resorcinol), which had an IC50 of 1.1 mmol/L. In contrast, Thiamidol only weakly inhibited mushroom tyrosinase (IC50 = 108 mmol/L), demonstrating the specificity of inhibition for human tyrosinase. In melanocyte cultures, Thiamidol strongly, but reversibly, inhibited melanin production (IC50 = 0.9 mmol/L), whereas hydroquinone irreversibly inhibited melanogenesis (IC50 = 16.3 mmol/L), demonstrating Thiamidol’s inhibition of melanin via tyrosinase inhibition as opposed to cytotoxicity. Clinically, Thiamidol visibly reduced the appearance of age spots within 4 weeks, and after 12 weeks, some age spots were indistinguishable from the normal adjacent skin. This data demonstrates the viability of Thiamidol as a suitable anti-melanogenic ingredient for use in topical cosmetic products.