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

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Abstract

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 H1 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 IC50 (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, H2-histaminergic, serotonergic, adrenergic receptor agonists or BaCl2. 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 H1 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.

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Acknowledgements

This study was funded by Sun Pharma Advanced Research Company Limited. All the authors are employed by Sun Pharma Advanced Research Company Limited.

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  1. Sun Pharma Advanced Research Company Limited, Atladara, Tandalja Road, Vadodara, Gujarat, India, 390 012

    Sanjay N. Mandhane, Upendra B. Ayer, Ajay S. Midha, Chitturi Trinadha Rao & Thennati Rajamannar

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  1. Sanjay N. Mandhane
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  2. Upendra B. Ayer
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Correspondence to Sanjay N. Mandhane.

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Mandhane, S.N., Ayer, U.B., Midha, A.S. et al. Preclinical Efficacy and Safety Pharmacology of SUN-1334H, a Potent Orally Active Antihistamine Agent. Drugs R&D 9, 93–112 (2008). https://doi.org/10.2165/00126839-200809020-00004

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