Carbonyl scavengers for skin protection from glycation

用于保护皮肤免受糖化作用的羰基清除剂

• 批准号: 6691130
• 负责人: ELAINE L JACOBSON
• 金额: $ 10万
• 依托单位: NIADYNE, INC.
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6691130
• 关键词: carbonyl compound; chemoprevention; drug design /synthesis /production; drug screening /evaluation; glycation; inhibitor /antagonist; oxidative stress; photoprotective agent; skin disorder; skin pharmacology; tissue /cell culture; topical drug application

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).

描述（由申请人提供）：该第一阶段 STTR 申请为糖化抑制剂的商业开发提供了技术基础，作为针对以糖化损伤增加为特征的病理性皮肤状况的新型保护剂。糖化是细胞成分与还原糖和其他反应性羰基物质 (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的内源性化学损伤的关键来源。学术和商业研究的目标是开发糖化的药理学抑制剂，但尽管皮肤是糖化病理学的重要靶组织，但没有治疗方法将皮肤作为糖化的关键靶点。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，可保护培养的人类皮肤细胞免受糖基化损伤。使用该原型药效团，将检查设计局部糖化抑制剂用于治疗性抑制源自代谢恶化、紫外线照射和时间老化的皮肤糖化损伤的可行性。合成具有优化亲脂性的原型糖化抑制剂的酯衍生物，用于局部皮肤递送（具体目标 1）（具体目标 1），随后将展示在急性羰基和光化应激下对重建人体皮肤的糖化损伤的保护作用（具体目标 2）。