ABSTRACT
The pre-clinical characterization of novel aryloxypyridine amides that are histamine H(3) receptor antagonists is described. These compounds are high affinity histamine H(3) ligands that penetrate the CNS and occupy the histamine H(3) receptor in rat brain. Several compounds were extensively profiled pre-clinically leading to the identification of two compounds suitable for nomination as development candidates.
Subject(s)
Azepines/pharmacology , Histamine H3 Antagonists/pharmacology , Pyridines/pharmacology , Amides/chemistry , Animals , Azepines/chemistry , Drug Evaluation, Preclinical , Pyridines/chemistry , RatsABSTRACT
Pre-clinical characterization of novel substituted pyrrolidines that are high affinity histamine H(3) receptor antagonists is described. These compounds efficiently penetrate the CNS and occupy the histamine H(3) receptor in rat brain following oral administration. One compound, (2S,4R)-1-[2-(4-cyclobutyl-[1,4]diazepane-1-carbonyl)-4-(3-fluoro-phenoxy)-pyrrolidin-1-yl]-ethanone, was extensively profiled and shows promise as a potential clinical candidate.
Subject(s)
Azepines/chemistry , Histamine H3 Antagonists/chemistry , Pyrrolidines/chemistry , Receptors, Histamine H3/chemistry , Administration, Oral , Animals , Azepines/chemical synthesis , Azepines/pharmacokinetics , Brain/metabolism , Dogs , Drug Evaluation, Preclinical , Histamine H3 Antagonists/chemical synthesis , Histamine H3 Antagonists/pharmacokinetics , Humans , Mice , Pyrrolidines/chemical synthesis , Pyrrolidines/pharmacokinetics , Rats , Receptors, Histamine H3/metabolism , Structure-Activity RelationshipABSTRACT
A novel series of imidazole containing histamine H(3) receptor ligands were investigated and found to be potent functional antagonists. After improving the stability of these molecules towards liver microsomes, these compounds were found to have no appreciable affinity for CYP P450s. Subsequent in vivo experiments showed significant brain uptake of (4-chloro-phenyl)-[2-(1-isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone 22.