Clinical doses of available H(1) antihistamines are limited mainly by sedative side effects. However, higher doses are often required to obtain optimal therapeutic activity, especially in dermatology. We report the synthesis of three norpiperidine imidazoazepines representative of a new class of selective and nonsedating H(1) antihistamines. The compounds were at least as potent as cetirizine and loratadine as measured by H(1) receptor binding affinity, by protection against compound 48/80- and histamine-induced lethality in rats and guinea pigs, respectively, and by skin reaction tests in rats, guinea pigs, and dogs. The compounds, in particular 3a, were less prone than the reference compounds to penetrate the brain and to occupy central H(1) receptors, suggesting absence of sedative side effects. In vitro and in vivo cardiovascular safety tests showed that 3a had no intrinsic potential to prolong ventricular repolarization or induce cardiac arrhythmias. Compound 3a has been selected for further clinical development, mainly for application in dermatology.