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

Abstract

We present the pharmacological and pharmacokinetic profiles of a novel histamine H 3 receptor antagonist, N- (3,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 M. SCH 79687 showed a 41-and 82-fold binding selectivity for the H 3 receptor over ␣ 2A -adrenoceptors and imidazoline I 2 , and Ͼ500-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 Ϯ 0.3. Similar H 3 antagonist activity was observed in the EFS cryopreserved and fresh tissue isolated human saphenous vein (HSV) assays (pK b ϭ 9.4 Ϯ 0.3 and 10.1 Ϯ 0.4). SCH 79687 (30 nM) did not block clonidine-induced inhibition of EFSinduced contractions in HSV. SCH 79687 (ED 50 ϭ 0.3 mg/kg i.v.) attenuated (R)-␣-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 ␣-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 g ⅐ 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.

4-(2-[2-(2(R)-Methylpyrrolidin-1-yl)ethyl]benzofuran-5-yl)benzonitrile and Related 2-Aminoethylbenzofuran H3 Receptor Antagonists Potently Enhance Cognition and Attention

“…In animal models, H 3 receptor antagonists have been shown to enhance attentive and cognitive behaviors, to enhance wakefulness, and when coadministered with H 1 antagonists to act as nasal decongestants . The molecular mechanisms whereby H 3 antagonists induce these effects are indirect and probably mediated by the enhanced release of neurotransmitters such as histamine, acetylcholine, dopamine, and others.…”

“…Two newer imidazole-based compounds, GT-2331 ( 5 ) and SCH-79876 13b ( 6 ), have also been described in the literature as potent H 3 receptor antagonists. Compound 6 , in combination with an H 1 antagonist, was active as a nasal decongestant in a feline model at 3−10 mg/kg 13a 1 Structures of histamine ( 1 ), imidazole-based H 3 antagonists 2 − 6 , and non-imidazole H 3 antagonists 7 − 13 . …”

Imetit Dihydrobromide and Thioperamide Medication in Cough Hypersensitivity Model—The Role of H<sub>3</sub> Receptors

“…H 3 receptor antagonists showed ability to inhibit nasal congestion in combination with antihistamines that target the H 1 receptor [18]. Combined therapy by SCH 79687 (H 3 R antagonist) and loratadine (H 1 R antagonist) showed anti-allergic and decongestant properties [19]. In other studies, combined therapy by PF-03654746 (H 3 R antagonist) and fexofenadine (H 1 R antagonist) in patients with AR led to suppression of all nasal symptoms induced by allergen [20] [21].…”

New antihistamines – perspectives in the treatment of some allergic and inflammatory disorders

“…However, observations from a preclinical model of nasal congestion (NC) showed that H3Rs along with H1Rs participated in the histamine-induced NC and demonstrated the sense of simultaneously blocking both H1 and H3 receptors in conditions with NC [67, 68]. Also, compound SCH-79687 is a highly potent H3R antagonist that reduced congestion in animal models of AR when co-administered with a H1R antagonist [69]. This supports the hypothesis that the efficacy of H3R antagonists is related to peripherally mediated release of norepinephrine from nasal mucosal H3 receptors, because SCH-79687 virtually does not penetrate the brain [70].…”