Mollison K W, Fey T A, Gauvin D M, Sheets M P, Smith M L, Pong M, Krause R, Miller L, Or Y S, Kawai M, Wagner R, Wiedeman P E, Clark R F, Gunawardana I W, Rhoades T A, Henry C L, Tu N P, BaMaung N Y, Kopecka H, Liu L, Xie Q, Lane B C, Trevillyan J M, Marsh K, Luly J R
Abbott Laboratories, Abbott Park, Illinois, USA.
Curr Pharm Des. 1998 Oct;4(5):367-79.
Drug therapy for the major inflammatory skin diseases, which include atopic dermatitis, psoriasis and allergic contact dermatitis, is often inadequate due to poor efficacy, toxicity, or both. Much research has focused on the macrolactam T cell inhibitors as a promising new class of agents for immunotherapy, and medicinal chemistry efforts to design novel ascomycin analogs have produced clinically promising agents. A synthetic program to modify the ascomycin nucleus to alter its physicochemical properties and promote systemic clearance is described. A biologic screening strategy to identify analogs with reduced systemic activity and rapid pharmacokinetic elimination led to identification of the clinical candidate, ABT-281. A swine contact hypersensitivity model was used as a stringent indicator of skin penetration as human doses of topical corticosteroids produced inhibition only in the 50% range and ED50 values were 100-fold less potent than in rat. Also, cyclosporine was confirmed to be topically inactive in swine, as seen in human. ABT-281 had topical potency equal to tacrolimus (FK506) despite a severalfold lower potency for inhibiting swine T cells in vitro, consistent with superior skin penetration. ABT-281 was found to have a shorter duration of action after i.v. dosing in monkeys using an ex vivo whole blood IL-2 production assay. Systemic potency was reduced by 30-fold or more in rat popliteal lymph node hyperplasia and contact hypersensitivity assays. Following i.v. or i.p. administration in the swine contact hypersensitivity model, ABT-281 was 19- and 61-fold less potent, respectively, than FK506. Pharmacokinetic studies showed that ABT-281 had a shorter half life and higher rate of clearance than FK506 in all three species. The potent topical activity and reduced systemic exposure of ABT-281 may thus provide both efficacy and a greater margin of safety for topical therapy of skin diseases.
针对包括特应性皮炎、银屑病和过敏性接触性皮炎在内的主要炎症性皮肤病的药物治疗，往往因疗效不佳、毒性问题或两者兼而有之而效果欠佳。许多研究都聚焦于大环内酯类T细胞抑制剂，将其作为一类有前景的新型免疫治疗药物，并且药物化学领域为设计新型子囊霉素类似物所做的努力已经产生了具有临床前景的药物。本文描述了一个修饰子囊霉素核心以改变其物理化学性质并促进全身清除的合成方案。一种生物筛选策略用于识别具有降低的全身活性和快速药代动力学消除的类似物，从而鉴定出临床候选药物ABT - 281。猪接触性超敏反应模型被用作皮肤渗透的严格指标，因为人用剂量的外用皮质类固醇仅在50%的范围内产生抑制作用，且其半数有效剂量（ED50）值的效力比在大鼠中低100倍。此外，正如在人体中所见，环孢素在猪身上被证实外用无活性。尽管ABT - 281在体外抑制猪T细胞的效力比他克莫司（FK506）低几倍，但其局部效力与他克莫司相当，这与它具有更好的皮肤渗透性一致。使用体外全血白细胞介素 - 2产生测定法发现，在猴子静脉注射给药后，ABT - 281的作用持续时间较短。在大鼠腘窝淋巴结增生和接触性超敏反应试验中，其全身效力降低了30倍或更多。在猪接触性超敏反应模型中静脉注射或腹腔注射后，ABT - 281的效力分别比FK506低19倍和61倍。药代动力学研究表明，在所有三个物种中，ABT - 281的半衰期比FK506短，清除率比FK506高。因此，ABT - 281强大的局部活性和降低的全身暴露可能为皮肤病的局部治疗提供疗效和更高的安全边际。
