Abstract

We present the pharmacological and pharmacokinetic profiles of a novel histamine H₃ receptor antagonist, N-(3,5-dichlorophenyl)-N′-[[4-(1H-imidazol-4-ylmethyl)phenyl]-methyl]-urea (SCH 79687). The H₃-receptor binding K_i values for SCH 79687 were 1.9 and 13 nM in the rat and guinea pig (GP), respectively. The K_i values for SCH 79687 at histamine H₁ and H₂ receptors were greater than 1 μM. SCH 79687 showed a 41- and 82-fold binding selectivity for the H₃ receptor over α_2A-adrenoceptors and imidazoline I₂, and >500-fold H₃ selectivity compared with over 60 additional receptors. The pA₂ value for SCH 79687 in the GP ileum electrical field-stimulated (EFS) contraction was 9.6 ± 0.3. Similar H₃ antagonist activity was observed in the EFS cryopreserved and fresh tissue isolated human saphenous vein (HSV) assays (pK_b = 9.4 ± 0.3 and 10.1 ± 0.4). SCH 79687 (30 nM) did not block clonidine-induced inhibition of EFS-induced contractions in HSV. SCH 79687 (ED₅₀ = 0.3 mg/kg i.v.) attenuated (R)-α-methylhistamine inhibition of sympathetic hypertensive responses in the GP. At the time of activity evaluation, the GP plasma SCH 79687 concentration was 25 ng/ml at the dose of 0.3 mg/kg i.v. In feline nasal studies, combined administration of SCH 79687 (3 mg/kg i.v.) and the H₁-antagonist loratadine (3 mg/kg i.v.), at individual doses that do not produce decongestion, inhibited the compound 48/80-induced congestion by 47%. The α-adrenergic agonist phenylpropanolamine (PPA; 1 mg/kg i.v.) also attenuated compound 48/80 nasal responses by 42%. Unlike the H₃/H₁ combination that did not affect blood pressure (BP), PPA (1 mg/kg i.v.) significantly increased BP compared with control animals by a maximum of 31 mm Hg. Orally, SCH 79687 (10 mg/kg) plus loratadine (10 mg/kg) also produced decongestion without effects on BP. In pharmacokinetic studies, oral dosing with SCH 79687 in the rat (10 mg/kg) and monkey (3 mg/kg) achieved plasma C_max and area under the curve values greater than 1.5 and 12.1 μg · h/ml, respectively. SCH 79687 is an orally active H₃ antagonist with a good pharmacokinetic profile that, in combination with an H₁ antagonist, demonstrates decongestant efficacy comparable with oral sympathomimetic decongestants but without hypertensive liabilities.