Pharmacological Characterization of the Novel Histamine H3-Receptor Antagonist N-(3,5-Dichlorophenyl)-N′-[[4-(1H-imidazol-4-ylmethyl)phenyl]-methyl]-urea (SCH 79687)

We present the pharmacological and pharmacokinetic profiles of a novel histamine H 3 receptor antagonist, N- (3,5-dichlorophenyl)- N ′-[[4-(1 H -imidazol-4-ylmethyl)phenyl]-methyl]-urea (SCH 79687). The H 3 -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 H 1 and H 2 receptors were greater than 1 μM. SCH 79687 showed a 41- and 82-fold binding selectivity for the H 3 receptor over α 2A -adrenoceptors and imidazoline I 2 , and >500-fold H 3 selectivity compared with over 60 additional receptors. The p A 2 value for SCH 79687 in the GP ileum electrical field-stimulated (EFS) contraction was 9.6 ± 0.3. Similar H 3 antagonist activity was observed in the EFS cryopreserved and fresh tissue isolated human saphenous vein (HSV) assays (p K 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 (ED 50 = 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 H 1 -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 H 3 /H 1 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 H 3 antagonist with a good pharmacokinetic profile that, in combination with an H 1 antagonist, demonstrates decongestant efficacy comparable with oral sympathomimetic decongestants but without hypertensive liabilities.