Identification of Mepenzolate Derivatives With Long-Acting Bronchodilatory Activity.

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

doi:10.3389/fphar.2018.00344

Abstract

The standard treatment for chronic obstructive pulmonary disease is a combination of anti-inflammatory drugs and bronchodilators. We recently found that mepenzolate bromide (MP), an antagonist for human muscarinic M3 receptor (hM3R), has both anti-inflammatory and short-acting bronchodilatory activities. To obtain MP derivatives with longer-lasting bronchodilatory activity, we synthesized hybrid compounds based on MP and two other muscarinic antagonists with long-acting bronchodilatory activity glycopyrronium bromide (GC) and aclidinium bromide (AD). Of these three synthesized hybrid compounds (MP-GC, GC-MP, MP-AD) and MP, MP-AD showed the highest affinity for hM3R and had the longest lasting bronchodilatory activity, which was equivalent to that of GC and AD. Both MP-GC and MP-AD exhibited an anti-inflammatory effect equivalent to that of MP, whereas, in line with GC and AD, GC-MP did not show this effect. We also confirmed that administration of MP-AD suppressed elastase-induced pulmonary emphysema in a mouse model. These findings provide important information about the structure-activity relationship of MP for both bronchodilatory and anti-inflammatory activities.

Highlights

Chronic obstructive pulmonary disease (COPD) is a serious health problem and the world’s fourth leading cause of death (Mannino and Kiriz, 2006)
The total number of leucocytes and the individual number of neutrophils in Bronchoalveolar Lavage Fluid (BALF) are indicators of pulmonary inflammatory responses; these increased after Porcine pancreatic elastase (PPE) treatment in a manner that could be partially suppressed by the simultaneous intratracheal administration of mepenzolate bromide (MP) (Table 2), as described previously (Tanaka et al, 2013, 2014)
To obtain MP derivatives with longer-acting bronchodilatory activity, we synthesized hybrid compounds based on MP and glycopyrronium bromide (GC) or aclidinium bromide (AD)

Summary

Introduction

Chronic obstructive pulmonary disease (COPD) is a serious health problem and the world’s fourth leading cause of death (Mannino and Kiriz, 2006). This disease state is defined by a progressive and not fully reversible airflow limitation and an abnormal inflammatory response (Rabe et al, 2007; Vestbo et al, 2013; Vogelmeier et al, 2017). For the clinical treatment of COPD, it is important to improve airflow limitations by inducing bronchodilation, and to hinder disease progression by suppressing inflammatory responses. LABAs and LAMAs (or combinations of the two) are used as first-line drugs for COPD treatment

Methods

Results

Conclusion