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Design of Phthalazinone Amide Histamine H1 Receptor Antagonists for Use in Rhinitis.

ABSTRACT: The synthesis of potent amide-containing phthalazinone H1 histamine receptor antagonists is described. Three analogues 3e, 3g, and 9g were equipotent with azelastine and were longer-acting in vitro. Amide 3g had low oral bioavailability, low brain-penetration, high metabolic clearance, and long duration of action in vivo, and it was suitable for once-daily dosing intranasally, with a predicted dose for humans of approximately 0.5 mg per day.

SUBMITTER: Procopiou PA 

PROVIDER: S-EPMC5430406 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Design of Phthalazinone Amide Histamine H<sub>1</sub> Receptor Antagonists for Use in Rhinitis.

Procopiou Panayiotis A PA   Ford Alison J AJ   Gore Paul M PM   Looker Brian E BE   Hodgson Simon T ST   Holmes Duncan S DS   Vile Sadie S   Clark Kenneth L KL   Saunders Ken A KA   Slack Robert J RJ   Rowedder James E JE   Watts Clarissa J CJ  

ACS medicinal chemistry letters 20170421 5

The synthesis of potent amide-containing phthalazinone H<sub>1</sub> histamine receptor antagonists is described. Three analogues <b>3e</b>, <b>3g</b>, and <b>9g</b> were equipotent with azelastine and were longer-acting in vitro. Amide <b>3g</b> had low oral bioavailability, low brain-penetration, high metabolic clearance, and long duration of action in vivo, and it was suitable for once-daily dosing intranasally, with a predicted dose for humans of approximately 0.5 mg per day. ...[more]

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