Novel quinuclidinyl heteroarylcarbamate derivatives as muscarinic receptor antagonists

Shinya Nagashima; Yuji Matsushima; Hisao Hamaguchi; Hiroshi Nagata; Toru Kontani; Ayako Moritomo; Tadatsura Koshika; Makoto Takeuchi

doi:10.1016/j.bmc.2014.04.031

Novel quinuclidinyl heteroarylcarbamate derivatives as muscarinic receptor antagonists

Bioorg Med Chem. 2014 Jul 1;22(13):3478-87. doi: 10.1016/j.bmc.2014.04.031. Epub 2014 Apr 24.

Authors

Shinya Nagashima¹, Yuji Matsushima², Hisao Hamaguchi², Hiroshi Nagata², Toru Kontani², Ayako Moritomo², Tadatsura Koshika², Makoto Takeuchi²

Affiliations

¹ Drug Discovery Research, Astellas Pharma Inc, 21, Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. Electronic address: shinya.nagashima@astellas.com.
² Drug Discovery Research, Astellas Pharma Inc, 21, Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.

PMID: 24837158
DOI: 10.1016/j.bmc.2014.04.031

Abstract

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.

Keywords: ASP9133; COPD; In vivo selectivity; Long acting muscarinic receptor antagonist.

MeSH terms

Animals
Carbamates / chemical synthesis
Carbamates / chemistry
Carbamates / pharmacology*
Dose-Response Relationship, Drug
Male
Models, Molecular
Molecular Structure
Quinuclidines / chemical synthesis
Quinuclidines / chemistry
Quinuclidines / pharmacology*
Rats
Rats, Sprague-Dawley
Receptor, Muscarinic M3 / antagonists & inhibitors*
Structure-Activity Relationship

Substances

Carbamates
Quinuclidines
Receptor, Muscarinic M3