Vol. 289, Issue 2, 1160-1168, May 1999

Development of trans-2-[1H-Imidazol-4-yl] Cyclopropane Derivatives as New High-Affinity Histamine H₃ Receptor Ligands

Clark E. Tedford, James G. Phillips, Rosilyn Gregory, Gary P. Pawlowski, Leena Fadnis, M. Amin Khan, Syed M. Ali, Michael K. Handley and Stephen L. Yates

Gliatech Inc., Cleveland, Ohio

Previously, a novel series of 1H-4-substituted imidazole compounds were described as potent and selective histamine (HA) H₃ receptor ligands (Yates et al., 1999). The present studies extend the structure-activity relationships for optimal HA H₃ receptor affinity and central nervous system penetration by incorporation of a conformationally restricted cyclopropane nucleus. Moreover, the current studies extend our understanding of ligand-receptor interactions at the HA H₃ receptor with the development of high affinity HA H₃ receptor antagonists containing a stereochemical presentation. Structure-activity relationships were established from in vitro HA H₃ receptor-binding affinities using [³H]N-methylhistamine and rat cortical tissue homogenates. Systematic optimization of multiple structural features critical for HA H₃ receptor affinity provided some of the most potent HA H₃ receptor agents described. For example, GT-2331 was determined to bind to a single population of HA H₃ receptors with a K_i of 0.125 nM. In vivo, GT-2331 has a favorable central nervous system penetration profile with an ED₅₀ of 0.08 mg/kg (i.p.) in rats and a long duration of action (T_1/2 > 4 h). In addition, GT-2331 was extremely selective for the HA H₃ receptor versus other HA receptors and a battery of neurotransmitter, neuropeptide, hormone, or enzyme systems. Several compounds were tested in vitro which suggested HA H₃ receptor heterogeneity and are discussed in terms of structure-activity relationships for the HA H₃ receptor.