NON-IRRITATING RETINOIDS FOR THE TREATMENT OF AGING

用于治疗衰老的无刺激性维A酸

• 批准号: 6691238
• 负责人: William Paul Purcell
• 金额: $ 9.9万
• 依托单位: MOLECULAR DESIGN INTERNATIONAL, INC.
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6691238
• 关键词: aging; biomaterial development /preparation; cell proliferation; clinical research; enzyme linked immunosorbent assay; histochemistry /cytochemistry; human subject; laboratory mouse; metalloendopeptidases; organ culture; procollagen; retinoids; skin

DESCRIPTION (provided by applicant): Molecular Design International, Inc. (MDI) has designed and synthesized three synthetic retinoids based on the removal of the free carboxylic acid proton and replacement with an ester moiety in 14-all trans retinoic acid (RA), 13-cis retinoic acid (13-cis RA) and 9-cis retinoic acid (9-cis RA), respectively. Based on our preliminary studies in the rhinomouse model, one of these agents (MDI-301; the 9-cis RA derivative) has activity in models that predict efficacy in treatment of acne and efficacy in dermal repair. At the same time, this molecule appears to be significantly less irritating than the natural retinoids. The primary goal of the Phase I studies is to extend these preliminary findings with MDI-301 from animal models to preclinical models with human organ-cultured skin. Another important but ancillary goal of the Phase I research is to begin elucidating the cellular and molecular basis for retinoid irritation in the skin. The use of a non-irritating synthetic agent in conjunction with the naturally-occurring analogues should provide significant insight into the mechanisms by which the naturally occurring agents produce irritation. To achieve the overall objectives of the Phase I studies, we will compare MDI-301 with RA for efficacy (i.e., increased epidermal and dermal proliferation, increased procollagen production and decreased elaboration of matrix metalloproteinases) and for induction of irritation in organ cultures of human skin. Finally, we will utilize the rhinomouse model to examine MDI-403 (13-cis RA derivative) and MDI-101 (RA derivative) for i) reduction of superficial cysts (utriculi) formation, ii) induction of dermal repair and iii) induction of skin irritation. If MDI-301 or either of the other two agents proves to have efficacy without producing irritation, they will provide strong candidates for replacement of currently used retinoids in topical applications.

描述（由申请人提供）： 分子设计国际公司(MDI)基于14-全反式维甲酸（RA）、13-顺式维甲酸（13-cis RA）和9-顺式维甲酸（9-cis RA）中游离羧酸质子的去除和酯基的取代，设计并合成了三种合成类维甲酸。基于我们在小鼠模型中的初步研究，这些药物之一（MDI-301; 9-顺式RA衍生物）在预测痤疮治疗功效和皮肤修复功效的模型中具有活性。同时，这种分子似乎比天然类维生素A的刺激性要小得多。I期研究的主要目标是将MDI-301的这些初步发现从动物模型扩展到人类器官培养皮肤的临床前模型。I期研究的另一个重要但辅助的目标是开始阐明类维生素A刺激皮肤的细胞和分子基础。与天然存在的类似物结合使用无刺激性的合成试剂应提供对天然存在的试剂产生刺激的机制的重要见解。 为了实现I期研究的总体目标，我们将比较MDI-301与RA的疗效（即，增加的表皮和真皮增殖、增加的前胶原产生和减少的基质金属蛋白酶的加工）和用于在人皮肤的器官培养物中诱导刺激。最后，我们将利用小鼠模型来检查MDI-403（13-顺式RA衍生物）和MDI-101（RA衍生物）i）减少浅表囊肿（椭圆囊）形成，ii）诱导皮肤修复和iii）诱导皮肤刺激。如果MDI-301或其他两种药物中的任何一种被证明具有有效性而不产生刺激性，则它们将为替代目前在局部应用中使用的类维生素A提供强有力的候选药物。