Discovery and Early Clinical Development of Isobutyl 1-[8-Methoxy-5-(1-oxo-3H-isobenzofuran-5-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxylate (LEO 39652), a Novel "Dual-Soft" PDE4 Inhibitor for Topical Treatment of Atopic Dermatitis.

We describe the design of a novel PDE4 scaffold and the exploration of the dual-soft concept to reduce systemic side effects via rapid elimination: introducing ester functionalities that can be inactivated in blood as well as by the liver (dual-soft) while being stable in human skin. Compound 40 was selected as a clinical candidate as it was potent and rapidly degraded by blood and liver to inactive metabolites and because in preclinical studies it showed high exposure at the target organ: the skin. Preclinical and clinical data are presented confirming the value of the dual-soft concept in reducing systemic exposure.

The acute and short-time effect of supplementation with the combination of n-3 fatty acids and acetylsalicylic acid on platelet function and plasma lipids.

Antiplatelet therapy with acetylsalicylic acid (ASA) is commonly used to reduce the risk of cardio- and cerebrovascular events. Fish consumption has been inversely related to coronary disease, which has been partly attributed to an inhibitory effect of n-3 polyunsaturated fatty acids (n-3 PUFA) on platelet production of tromboxane A2. In this study, we investigated the acute and short-time effect of supplementation with n-3 PUFA and intravenous ASA on platelet function, platelet fatty acid composition and plasma lipids. Eighteen healthy men were randomly allocated to a daily intake of 10 g n-3 PUFA or placebo. After this supplement (14 h and 14 days), blood was sampled before and after intravenous injection of 100 mg ASA. n-3 PUFA given for 14 days caused a minor inhibition of platelet reactivity but negligible compared to 100 mg ASA. No additive effect of n-3 PUFA and ASA could be demonstrated.