671 Discovery of LEO 39652 a novel PDE4 inhibitor for topical treatment of atopic dermatitis

Abstract

Topical treatment of severe atopic dermatitis frequently requires application of drug to more than 30% of the body surface area of the patient. The atopic skin barrier is highly compromised and thus there is a risk that a large portion of the applied dose will reach the systemic circulation, leading to a significant systemic load of the applied compound. Previously we have described the discovery of LEO 29102, a “soft” PDE4 inhibitor designed to achieve high local skin concentrations but low systemic exposure upon topical application, due to a high systemic clearance driven by rapid liver metabolism.[1] In the end, the clinical development of this compound was however discontinued in part due to safety concerns related to the systemic exposure of the candidate drug. Here we wish to describe our effort to reduce even further the systemic compound exposure observed upon topical administration, an exercise with the aim of minimizing the risk of target-related, systemic side effects. The approach was to benefit from esterase-mediated compound degradation in compartments like the blood. Despite the fact that tissue distribution in humans is not fully characterized for all esterases, some differences in expression levels in for instance skin versus blood have been reported. Thus it was hypothesized that it should be possible to identify ester-containing compounds suitable for topical delivery. Compounds that should be sufficiently stable in skin to provide the desired pharmacological effect but at the same time they should be rapidly degraded both in blood and by the liver. Here we report the discovery of a novel series of PDE4 inhibitors and our efforts to optimize the in vitro pharmacokinetics of these using phenotypic screening models of skin and blood stability. Eventually LEO 39652 was selected as a clinical development candidate and a characterization of its metabolism, pharmacokinetic profile as well as the early clinical efficacy data obtained with this compound will be presented in this poster.[1] J. Med. Chem., 2014, 57 (14), 5893–5903