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Chemical Modification-Mediated Optimisation of Bronchodilatory Activity of Mepenzolate, a Muscarinic Receptor Antagonist With Anti-Inflammatory Activity

Chemical Modification-Mediated Optimisation of Bronchodilatory Activity of Mepenzolate, a Muscarinic Receptor Antagonist With Anti-Inflammatory Activity

Yasunobu Yamashita, Ken-Ichiro Tanaka, Naoki Yamakawa, Teita Asano, Yuki Kanda, Ayaka Takafuji, Masahiro Kawahara, Mitsuko Takenaga, Yoshifumi Fukunishi, Tohru Mizushima

Bioorg Med Chem. 2019 Aug 1;27(15):3339-3346.

PMID: 31204225

Abstract:

The treatment for patients with chronic obstructive pulmonary disease (COPD) usually involves a combination of anti-inflammatory and bronchodilatory drugs. We recently found that mepenzolate bromide (1) and its derivative, 3-(2-hydroxy-2, 2-diphenylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide (5), have both anti-inflammatory and bronchodilatory activities. We chemically modified 5 with a view to obtain derivatives with both anti-inflammatory and longer-lasting bronchodilatory activities. Among the synthesized compounds, (R)-(-)-12 ((R)-3-(2-hydroxy-2,2-diphenylacetoxy)-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane bromide) showed the highest affinity in vitro for the human muscarinic M3 receptor (hM3R). Compared to 1 and 5, (R)-(-)-12 exhibited longer-lasting bronchodilatory activity and equivalent anti-inflammatory effect in mice. The long-term intratracheal administration of (R)-(-)-12 suppressed porcine pancreatic elastase-induced pulmonary emphysema in mice, whereas the same procedure with a long-acting muscarinic antagonist used clinically (tiotropium bromide) did not. These results suggest that (R)-(-)-12 might be therapeutically beneficial for use with COPD patients given the improved effects seen against both inflammatory pulmonary emphysema and airflow limitation in this animal model.

Chemicals Related in the Paper:

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AP134640850	2,3-Dimethylphenylmagnesium bromide	134640-85-0	Price
AP185416175	3,5-Dimethyl-4-methoxyphenylmagnesium bromide	185416-17-5	Price
AP30897860	2,5-Dimethylphenylmagnesium bromide	30897-86-0	Price

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