Kojic acid derivatives as histamine H_3 receptor ligands

摘要

The histamine H_3 receptor (H_3R) is a promising target in the development of new compounds for the treatment of mainly centrally occurring diseases. However, emerging novel therapeutic concepts have been introduced and some indications in the H_3R field, e.g. migraine, pain or allergic rhinitis, might take advantage of peripherally acting ligands. In this work, kojic acid-derived structural elements were inserted into a well established H_3R antagonist/inverse agonist scaffold to investigate the bioisosteric potential of γ-pyranones with respect to the different moieties of the H_3R pharmacophore. The most affine compounds showed receptor binding in the low nanomolar concentration range. Evaluation and comparison of kojic acid-containing ligands and their corresponding phenyl analogues (3-7) revealed that the newly integrated scaffold greatly influences chemical properties (S Log P, topological polar surface area (tPSA)) and hence, potentially modifies the pharmacokinetic profile of the different derivatives. Benzyl-1-(4-(3-(piperidin-1-yl)propoxy)phenyl)methanamine ligands 3 and 4 belong to the centrally acting diamine-based class of H_3R antagonist/inverse agonist, whereas kojic acid analogues 6 and 7 might act peripherally. The latter compounds state promising lead structures in the development of H_3R ligands with a modified profile of action.