Novel quinuclidinyl heteroarylcarbamate derivatives as muscarinic receptor antagonists

A novel quinuclidinyl heteroarylcarbamate derivative ASP9133 was identified as a long-acting muscarinic antagonist (LAMA) showing more selective inhibition of bronchoconstriction against salivation and more rapid onset of action than tiotropium bromide. Herein, we describe the synthesis and pharmaco...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2014-07, Vol.22 (13), p.3478-3487
Main Authors: Nagashima, Shinya, Matsushima, Yuji, Hamaguchi, Hisao, Nagata, Hiroshi, Kontani, Toru, Moritomo, Ayako, Koshika, Tadatsura, Takeuchi, Makoto
Format: Article
Language:English
Subjects:
Animals
ASP9133
Carbamates - chemical synthesis
Carbamates - chemistry
Carbamates - pharmacology
COPD
Dose-Response Relationship, Drug
In vivo selectivity
Long acting muscarinic receptor antagonist
Male
Models, Molecular
Molecular Structure
Quinuclidines - chemical synthesis
Quinuclidines - chemistry
Quinuclidines - pharmacology
Rats
Rats, Sprague-Dawley
Receptor, Muscarinic M3 - antagonists & inhibitors
Structure-Activity Relationship
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Summary:A novel quinuclidinyl heteroarylcarbamate derivative ASP9133 was identified as a long-acting muscarinic antagonist (LAMA) showing more selective inhibition of bronchoconstriction against salivation and more rapid onset of action than tiotropium bromide. Herein, we describe the synthesis and pharmacological profiles of novel quinuclidinyl heteroarylcarbamate derivatives. Among them, the quinuclidin-4-yl thiazolylcarbamate derivative ASP9133 was identified as a promising long-acting muscarinic antagonist (LAMA) showing more selective inhibition of bronchoconstriction against salivation and more rapid onset of action in a rat model than tiotropium bromide.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2014.04.031