Discovery of ascomycin analogs with potent topical but weak
systemic activity for treatment of inflammatory skin diseases.
Mollison KW, Fey TA, Gauvin DM, Sheets MP, Smith ML, Pong M, Krause R, Miller
L, Or YS, Kawai M, Wagner R, Wiedeman PE, Clark RF, Gunawardana IW, Rhoades TA,
Henry CL, Tu NP, BaMaung NY, Kopecka H, Liu L, Xie Q, Lane BC, Trevillyan JM,
Marsh K, Luly JR, et al.
Abbott Laboratories, Abbott Park, Illinois, USA. karl.mollison@abbott.com
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.
