Histamine H 3 and H 4 receptor affinity of branched 3-(1H-imidazol-4-yl)propyl N-alkylcarbamates Dorota La _ zewska a , Małgorzata Wie ˛cek a , Xavier Ligneau b , Tim Kottke c , Lilia Weizel c , Roland Seifert d , Walter Schunack e , Holger Stark c , Katarzyna Kiec ´ -Kononowicz a, * a Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, ul. Medyczna 9, 30-688 Kraków, Poland b Bioprojet-Biotech, 4 rue du Chesnay Beauregard, BP 96205, 35762 Saint-Grégoire, France c Institute of Pharmaceutical Chemistry, Johann Wolfgang Goethe-University, Max-von-Laue-Strasse 9, 60438 Frankfurt/Main, Germany d Institute of Pharmacology, Medical School of Hannover, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany e Institute of Pharmacy, Free University of Berlin, Königin-Luise-Strasse 2+4, 14195 Berlin, Germany article info Article history: Received 23 June 2009 Revised 30 September 2009 Accepted 1 October 2009 Available online 6 October 2009 Keywords: Histamine H 3 receptor Histamine H 4 receptor Imidazole derivatives abstract A series of imidazole-containing (non-)chiral carbamates were tested at human histamine H 3 receptor (H 3 R). All compounds displayed K i values below 100 nM. A trend for a stereoselectivity at human H 3 R was observed for the chiral a-branched ligands. Selected compounds were also tested at human hista- mine H 4 receptor and showed moderate to weak affinities (118–1460 nM). Ó 2009 Elsevier Ltd. All rights reserved. Imidazole moiety is present in many biologically active com- pounds (for review see 1 ). One of the most important of them is his- tamine. Histamine exerts tremendous influence over a variety of physiological processes by the four known receptors subtypes: H 1 ,H 2 ,H 3 and H 4 . Histamine H 3 receptors (H 3 Rs) are widely expressed in CNS and play the main role in many important processes. Nowadays, the cur- rent interest in the area of H 3 R ligands (inverse agonists, antagonists) is focused on non-imidazole compounds (for review see 2–7 ), whereas the first generation H 3 R active structures contained the imidazole moiety (for review see 8 ). These compounds were ana- logues of histamine with the 4-substituted imidazole ring. However, despite their high potency and clinical studies none of them have en- tered the market as a drug. The main drawback of these compounds was inhibition of numerous CYP450 enzymes 9,10 (although recently some studies suggested the possibilities to minimize these activi- ties 11 ), reduced oral bioavailability and poor brain penetration (e.g., thioperamide 12 ). Actually, imidazole-based ligands like thio- peramide, clobenpropit, and ciproxifan (Fig. 1) are mainly used as reference structures in a variety of preclinical animal models. Despite that imidazole-containing ligands are further the subject of investigations and quite recently, Jablonowski et al. de- scribed a series of N-methylimidazole-containing compounds—po- tent H 3 R ligands with improved metabolic stability. (e.g., 1, Fig. 2) 13 Histamine H 4 receptors (H 4 Rs) are preferentially expressed on hematopoietic and immune cells (e.g., eosinophils, mast cells, mac- rophages) and play a role in immunological and inflammatory processes. 14 The human H 4 R is closely related to the human H 3 R. These two proteins have a sequence identity of 31% and their homology in the transmembrane region is 54%. 15 Therefore, it is not surprising, that numerous imidazole-con- taining H 3 R ligands have also significant affinity for the human H 4 R (e.g., Table 1) 16 and some of them (e.g., thioperamide, cloben- propit) have been used to characterize the H 4 R. While the current medicinal chemistry efforts are concerned at finding more selec- tive compounds, AstraZeneca continues to develop imidazole derivatives acting as dual H 3 R and H 4 R ligands (e.g., Fig. 3). 17 These compounds are considered as potential drugs for the treatment of histamine H 4 mediated diseases especially asthma. Also, very recently, Igel et al. described N G -alkanoyl-imidazolylpropylguani- dines as high-affinity human H 3 R antagonists/partial agonists and full H 4 R agonists. 18 For example, UR-PI294 with N G -propionyl group, was tritiated, resulting the radioligand [ 3 H]UR-PI294. 19 This radioligand is considered a valuable pharmacological tool for the determination of human H 3 R and human H 4 R affinities. In this Letter, we describe human H 3 R affinity of branched 3-(1H-imidazol-4-yl)-propyl N-alkylcarbamates (Scheme 1). Most 0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2009.10.005 * Corresponding author. Tel.: +48 12 620 55 81; fax: +48 12 620 55 96. E-mail address: mfkonono@cyf-kr.edu.pl (K. Kiec ´ -Kononowicz). Bioorganic & Medicinal Chemistry Letters 19 (2009) 6682–6685 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl