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 N'-[[4-(1H-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 muM. SCH 79687 showed a 41- and 82-fold binding selectivity for the H-3 receptor over alpha(2A)-adrenoceptors and imidazoline I-2, and >500-fold H-3 selectivity compared with over 60 additional receptors. The pA(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 (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)-alpha-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 alpha-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 mug . 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.