Design and synthesis of histamine H3/H4 receptor ligands with a cyclopropane scaffold. Issue 23 (15th December 2018)

• Record Type: Journal Article
• Authors: Watanabe, Mizuki; Kobayashi, Takaaki; Ito, Yoshihiko; Fukuda, Hayato; Yamada, Shizuo; Arisawa, Mitsuhiro; Shuto, Satoshi
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 28:Issue 23/24(2018)
• Page Start: 3630
• Page End: 3633
• Publication Date: 2018-12-15
• Subjects: Histamine -- GPCR -- H3 receptor -- H4 receptor -- Antagonist -- Cyclopropane; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2018.10.041
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Highlights: A new series of cyclopropane-based histamine analogs were designed and synthesized. Compounds12 and13 bound to both the H3 and H4 receptors. Their affinities were comparable to a well-known H3 /H4 antagonist, thioperamide. Abstract: We previously designed and synthesized a series of histamine analogues with an imidazolylcyclopropane scaffold and identified potent non-selective antagonists for histamine H3 and H4 receptor subtypes. In this study, to develop H4 selective ligands, we newly designed and synthesized cyclopropane-based derivatives having an indole, benzimidazole, or piperazine structure, which are components of representative H4 selective antagonists such as JNJ7777120 and JNJ10191584. Among the synthesized derivatives, imidazolylcyclopropanes12 and13 conjugated with a benzimidazole showed binding affinity to the H3 and H4 receptors comparable to that of a well-known non-selective H3 /H4 antagonist, thioperamide. These results suggest that the binding modes of the cyclopropane-based H3 /H4 ligands in the H4 receptor can be different from those of the indole/benzimidazole-piperazine derivatives.