Preclinical efficacy and safety pharmacology of SUN-1334H, a potent orally active antihistamine agent.

Abstract

OBJECTIVE:

These studies aimed to outline the in vitro and in vivo histamine H(1) receptor antagonistic activity and safety pharmacology of SUN-1334H, a new potent antihistamine agent under clinical development.

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 histamine-induced contractions of isolated guinea-pig ileum with an IC(50) (half the maximal inhibitory concentration) of 0.198 micromol/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 micromol/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.

• Authors: Sanjay N Mandhane, Upendra B Ayer, Ajay S Midha, Chitturi Trinadha Rao, Thennati Rajamannar
• Journal: Drugs in R&D (Drugs R D) Vol. 9 Issue 2 Pg. 93-112 ( 2008) ISSN: 1174-5886 [Print] New Zealand
• PMID: 18298128 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 4-(4-(bis(4-fluorophenyl)methyl)piperazin-1-ylbut-2-enyloxy)acetic acid
• Acetates
• Histamine H1 Antagonists
• Piperazines
• Ovalbumin

Topics

• Acetates (pharmacokinetics, pharmacology)
• Animals
• Bronchoconstriction (drug effects)
• CHO Cells
• Cricetinae
• Cricetulus
• Dogs
• Electrocardiography (drug effects)
• Female
• Guinea Pigs
• Heart Rate (drug effects)
• Histamine H1 Antagonists (pharmacokinetics, pharmacology)
• Male
• Mice
• Ovalbumin (immunology)
• Piperazines (pharmacokinetics, pharmacology)
• Rats
• Rats, Sprague-Dawley
• Rhinitis (drug therapy)