DISCOVERY OF ASCOMYCIN ANALOGS WITH POTENT TOPICAL BUT WEAK SYSTEMIC ACTIVITY FOR TREATMENT OF INFLAMMATORY SKIN DISEASES

Drug therapy for the major inflammatory skin diseases, which include a topic 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 physico chemical properties and promote systemic clearance is described. A bio logic screening strategy to identify analogs with reduced systemic act ivity and rapid pharmacokinetic elimination led to identification of t he 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 a nd ED50 values were 100-fold less potent than in rat. Also, cyclospori ne was confirmed to be topically inactive in swine, as seen in human. ABT-281 had topical potency equal to tacrolimus (FK506)despite a sever alfold lower potency for inhibiting swine T cells in vitro, consistent with superior skin penetration. ABT-281 was found to have a shorter d uration 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 o r more in rat popliteal lymph node hyperplasia and contact hypersensit ivity assays. Following i.v. or i.p. administration in the swine conta ct hypersensitivity model, ABT-281 was 19- and 61-fold less potent, re spectively, than FK506. Pharmacokinetic studies showed that ABT-281 ha d a shorter half life and higher rate of clearance than FK506 in all t hree species. The potent topical activity and reduced sytemic exposure of ABT-281 may thus provide both efficacy and a greater margin of saf ety for topical therapy of skin disease's.