ABSTRACT
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.
Subject(s)
Dermatitis, Atopic/drug therapy , Phosphodiesterase 4 Inhibitors/pharmacology , Animals , Drug Discovery , Humans , Phosphodiesterase 4 Inhibitors/therapeutic useABSTRACT
The known KDR inhibitor SU5416 and several analogues of the indolin-2-one family were surprisingly found to be highly efficacious in the EAE model, an established model for multiple sclerosis. The high in vivo effect could be correlated to in vitro inhibition of the pro-inflammatory cytokine IL-2. Activity following po administration was obtained with several analogues and via the use of prodrugs.
Subject(s)
Encephalomyelitis, Autoimmune, Experimental/metabolism , Indoles/chemical synthesis , Multiple Sclerosis/metabolism , Animals , Encephalomyelitis, Autoimmune, Experimental/drug therapy , In Vitro Techniques , Indoles/chemistry , Indoles/pharmacology , Interleukin-2/antagonists & inhibitors , Interleukin-2/biosynthesis , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/metabolism , Mice , Multiple Sclerosis/drug therapy , Structure-Activity Relationship , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitorsABSTRACT
This paper describes how the introduction of "cationic" aliphatic amino groups in the chalcone scaffold results in potent antibacterial compounds. It is shown that the most favorable position for the aliphatic amino group is the 2-position of the B-ring, in particular in combination with a lipophilic substituent in the 5-position of the B-ring. We demonstrate that the compounds act by unselective disruption of cell membranes. Introduction of an additional aliphatic amino group in the A-ring results in compounds that are selective for bacterial membranes combined with a high antibacterial activity against both Gram-positive and -negative pathogens. The most potent compound in this study (78) has an MIC value of 2 muM against methicillin resistant Staphylococus aureus.
