Asymmetric synthesis and histamine receptor activity of new H1-receptor agonists and conformationally restricted H3-receptor antagonists

Abstract

Histamine H1-Receptor (H1R) Ligands: Developing highly potent and selective histamine H1-receptor (H1R) agonists has been an arduous task for several decades. Highly potent and selective H1R agonists are in demand for pharmacological and molecular investigation. Recently, the histaprodifens, a family of 2-(3,3-diphenylpropyl)-substituted histamine derivatives, have been established as new class of potent and selective H1R agonists. On this basis, new analogues of histaprodifen with polar side chains have been stereoselectively synthesized and evaluated as H1R agonists. As a key transformation the asymmetric aminohydroxylation has been used and successfully realized for the first time on an imidazole derivative. While all chiral analogues proved to be weak H1R antagonists, an achiral keto derivative of histaprodifen turned out to be the first 2-acylated histamine congener displaying partial H1R agonism. Moreover, the hydroxy analogue of this keto histaprodifen also showed partial H1R agonism indicating the potential of the 2-position in the histaprodifens for further modification. Histamine H3-Receptor (H3R) Ligands: The therapeutic importance of H1R and H2R agonists and especially antagonists is unquestioned since long. Antagonists that target H1R or H2R and are used in the treatment of allergic conditions, such as rhinitis, or of gastric acid release disorders, have been �blockbuster� drugs for many years. In view of this blockbuster status of the H1R and H2R antagonists, current expectations for the therapeutic potential of drugs that target the H3 and H4 receptors are high. Recent developments in the medicinal chemistry field of H3R antagonists have generated numerous compounds that are highly active in vitro and also in vivo. Looking at the extensive history of structure-activity relationships of H3R antagonists, rigid antagonists fulfil many criteria, display very high potency, and have apparently reached clinical studies. Keeping this view in mind, many diverse and conformationally restricted compounds have been developed. Moreover, the synthesis of a series of cyclopropanated analogues with different linker has been described in an efficient way. All novel compounds were screened for H3R antagonistic activity on guinea-pig ileum. It has been shown that attempts to rigidize flexible H3R antagonists, such as FUB-372 and/or iodoproxyfan, have ultimately led to a more or less severe attenuation of H3R affinity