Carbonyl scavengers for skin protection from glycation

描述（由申请人提供）：本I期STTR申请为糖基化抑制剂的商业化开发提供了技术基础，糖基化抑制剂作为针对以糖基化损伤增加为特征的病理性皮肤状况的新型保护剂。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，已被确定为内源性化学损伤的关键来源，有助于糖尿病、动脉粥样硬化、癌症转移和时间衰老等病理。学术和商业研究的目标是开发糖基化的药理学抑制剂，但没有治疗方法关注皮肤作为糖基化的关键靶点，尽管皮肤是糖基化病理的重要靶组织。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，可保护培养的人皮肤细胞免受糖基化损伤。利用这个原型药效团，设计局部糖基化抑制剂来治疗性抑制皮肤糖基化损伤的可行性将被检验，糖基化损伤是由代谢恶化、紫外线照射和时间老化引起的。原型糖基化抑制剂的酯衍生物的合成具有优化的亲脂性，用于局部皮肤递送（特定目的1），随后将展示在急性羰基和光化应激下重建的人体皮肤中对糖基化损伤的保护（特定目的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).