Carbonyl scavengers for skin protection from glycation

描述（由申请人提供）：本I期STTR申请为糖化抑制剂的商业开发提供了技术基础，糖化抑制剂可作为针对以糖化损伤增加为特征的病理性皮肤病的新型保护剂。糖基化是细胞成分与还原糖和其他活性羰基物质（RCS）的自发反应，已被确定为导致糖尿病、动脉粥样硬化、癌症转移和时间老化等病理学的内源性化学损伤的关键来源。学术和商业研究旨在开发糖化的药理学抑制剂，但没有治疗方法将皮肤作为糖化的关键靶点，尽管皮肤是糖化病理学的重要靶组织。最近，α-氨基-β-巯基-β，β-二甲基-乙烷被鉴定为有效的糖基化抑制剂药效团并获得专利，保护培养的人类皮肤细胞免受糖基化损伤。使用这个原型药效团的可行性设计的局部糖基化抑制剂的治疗抑制糖基化损伤的皮肤源于代谢恶化，紫外线照射，和时间老化将进行检查。合成具有优化亲脂性的用于局部皮肤递送的原型糖化抑制剂的酯衍生物（具体目标1）之后，将证明在急性羰基和光化应激下重建的人皮肤中对糖化损伤的保护作用（具体目标2）。

DESCRIPTION (provided by applicant): This phase I STTR application provides the technical basis for the commercial development of glycation inhibitors as novel protective agents against pathological skin conditions characterized by increased glycation damage. Glycation, the spontaneous reaction of cellular constituents with reducing sugars and other reactive carbonyl species (RCS), has been identified as a key source of endogenous chemical damage contributing to pathologies such as diabetes, atherosclerosis, cancer metastasis, and chronological aging. Academic and commercial research aims towards the development of pharmacological inhibitors of glycation, but no therapeutic approaches have focused on skin as a key target of glycation even though skin is an important target tissue for glycation pathology. Recently, alpha-amino-beta-mercapto-beta,beta-dimethyl-ethane was identified and patented as potent glycation inhibitor pharmacophore, protecting cultured human skin cells against glycation damage. Using this prototype pharmacophore the feasibility of designing topical glycation inhibitors for the therapeutic suppression of glycation damage in skin originating from metabolic deterioration, UV-irradiation, and chronological aging will be examined. The synthesis of ester-derivatives of the prototype glycation inhibitor with optimized lipophilicity for topical skin delivery (specific aim 1) will be followed by the demonstration of protection against glycation damage in reconstructed human skin under acute carbonyl and actinic stress (specific aim 2).