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

被引：14

作者：

Procopiou, Panayiotis A. ^{[1
]}

Ford, Alison J. ^{[2
]}

Gore, Paul M. ^{[1
]}

Looker, Brian E. ^{[1
]}

Hodgson, Simon T. ^{[1
]}

Holmes, Duncan S. ^{[1
]}

Vile, Sadie ^{[1
]}

Clark, Kenneth L. ^{[2
]}

Saunders, Ken A. ^{[2
]}

Slack, Robert J. ^{[2
]}

Rowedder, James E. ^{[3
]}

Watts, Clarissa J. ^{[4
]}

机构：

[1] GlaxoSmithKline Med Res Ctr, Med Chem, Gunnels Wood Rd, Stevenage SG1 2NY, Herts, England

[2] GlaxoSmithKline Med Res Ctr, Resp Biol, Gunnels Wood Rd, Stevenage SG1 2NY, Herts, England

[3] GlaxoSmithKline Med Res Ctr, R&D Platform Technol & Sci, Gunnels Wood Rd, Stevenage SG1 2NY, Herts, England

[4] GlaxoSmithKline Med Res Ctr, Drug Metab & Pharmacokinetcs, Gunnels Wood Rd, Stevenage SG1 2NY, Herts, England

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2017年 / 8卷 / 05期

关键词：

Histamine H-1 receptor antagonist; allergic rhinitis; once-daily dosing; topical application; phthalazinone; ALLERGIC RHINITIS; ANTIHISTAMINE;

D O I：

10.1021/acsmedchemlett.7b00112

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The synthesis of potent amide-containing phthalazinone H-1 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.

引用

页码：577 / 581

页数：5

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