Preclinical Efficacy and Safety Pharmacology of SUN-1334H, a Potent Orally Active Antihistamine Agent

• Published in: Drugs in R&D Vol. 9; no. 2; pp. 93 - 112
• Main Authors: Mandhane, Sanjay N., Ayer, Upendra B., Midha, Ajay S., Rao, Chitturi Trinadha, Rajamannar, Thennati
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 2008
• Subjects: Acetates - pharmacokinetics; Acetates - pharmacology; Animals; Bronchoconstriction - drug effects; CHO Cells; Cricetinae; Cricetulus; Dogs; Electrocardiography - drug effects; Female; Guinea Pigs; Heart Rate - drug effects; Histamine H1 Antagonists - pharmacokinetics; Histamine H1 Antagonists - pharmacology; Internal Medicine; Male; Medicine; Medicine & Public Health; Mice; Original Research Article; Ovalbumin - immunology; Pharmacology/Toxicology; Pharmacotherapy; Piperazines - pharmacokinetics; Piperazines - pharmacology; Rats; Rats, Sprague-Dawley; Rhinitis - drug therapy; Terfenadine; Loratadine; Astemizole; Desloratadine; Ebastine
• ISSN: 1174-5886; 1179-6901
• DOI: 10.2165/00126839-200809020-00004

Methods:
In vitro
antihistamine activity and selectivity of SUN-1334H was evaluated in a panel of receptor and enzyme assays and functional assays using isolated tissues.
In vivo
antihistamine and antiallergy efficacy were assessed following oral administration of SUN-1334H in histamine-induced bronchoconstriction in guinea pigs, skin wheal in beagle dogs and ovalbumin-induced rhinitis (sneezing, vascular permeability and intranasal pressure) in guinea pigs. Cardiovascular safety was assessed by CHO-K1/human ether-à-go-go related gene (hERG) K+ current assay, dog telemetry and guinea-pig ECG. CNS safety was assessed by functional observational battery in rats and pentobarbital-induced sedation and pentylenetetrazol-induced convulsions in mice. The effect on intestinal motility was assessed in rats.
Results:
In vitro
receptor binding assays showed that SUN-1334H had high histamine H
1
receptor binding affinity with an inhibition constant value of 9.7 nmol/L and either no or insignificant affinity with a panel of receptors and enzymes. In functional assays, SUN-1334H caused potent inhibition of histamineinduced contractions of isolated guinea-pig ileum with an IC
50
(half the maximal inhibitory concentration) of 0.198 μmol/L. In contrast, SUN-1334H had no significant effect on isolated tissue contractions induced by cholinergic, H
2
-histaminergic, serotonergic, adrenergic receptor agonists or BaCl
2
. In studies of animal models of histamine-mediated disorders, SUN-1334H potently inhibited histamine-induced bronchospasm over 24 hours following oral administration and completely suppressed histamine-induced skin wheal in beagle dogs and ovalbumin-induced rhinitis in guinea pigs. In CHO-K1/hERG cells, SUN-1334H did not modulate hERG K+-currents at concentrations as high as 100 μmol/L. Cardiovascular and CNS function and intestinal motility were not altered at doses several-fold greater than those required for efficacy, indicating a good safety profile of the drug.
Conclusions:
SUN-1334H is a potent, orally active, highly selective H
1
receptor antagonist with a long duration of action in its preclinical profile. It has potential for the treatment of disorders involving histamine as a mediator.