WY-49051

In an effort to develop an orally active, non‐sedating H1‐antagonist, compound Wy‐49,051 was synthesized and examined in various in vivo and in vitro assays. In vitro, the compound possessed high affinity for H1 receptors (IC50 = 44 nM) and was found to competitively antagonize histamine‐induced guinea pig ileum contraction. At a concentration of 1 × 10−10 M, Wy‐49,051 shifted the histamine dose‐response curve to the right in a parallel fashion. Wy‐49,051 demonstrated H1 antagonism in a variety of in vivo tests. Wy‐49,051 (s.c.) protected against histamine‐induced death (guinea pig) in a dose‐dependent manner and with a longer duration of action than terfenadine. In addition, Wy‐49,051 effectively antagonized histamine‐induced wheal formation (administered up to 18 hr prior to challenge) and was more potent than astemizole and chlorpheniramine. At a dose of 5 mg/kg (p.o.), Wy‐49,051 produced less inhibition of in vivo brain [3H]pyrilamine binding than ebastine (5 mg/kg, p.o.), terfenadine (20 mg/kg, p.o.), and chlorpheniramine (100 mg/kg, p.o.). Importantly, Wy‐49,051 did not exhibit H2‐antagonist activity (as indicated by a lack of effect on gastric acid secretion in the pylorus‐ligated rat) and did not affect histamine‐induced changes in blood pressure and heart rate in the anesthetized guinea pig. Although Wy‐49,051 displayed significant alpha1‐receptor affinity in vitro (IC50 =8 nM), it did not alter blood pressure or heart rate in SHR rats at doses examined above its projected therapeutic dose for H1‐receptor antagonism. Wy‐49,051 did not affect carbachol‐induced guinea pig ileum contraction and possessed little affinity for M2 muscarinic receptors (IC50 = 7.3 μ). Taken together with the previously mentioned in vivo [3H]pyrilamine binding data, these data indicate that Wy‐49,051 is a long‐acting, potent H1‐antagonist with less potential for sedative and anticholinergic side effects than many common antihistamines including chlorpheniramine.