Chemical modification-mediated optimisation of bronchodilatory activity of mepenzolate, a muscarinic receptor antagonist with anti-inflammatory activity. Issue 15 (1st August 2019)

• Record Type: Journal Article
• Authors: Yamashita, Yasunobu; Tanaka, Ken-ichiro; Yamakawa, Naoki; Asano, Teita; Kanda, Yuki; Takafuji, Ayaka; Kawahara, Masahiro; Takenaga, Mitsuko; Fukunishi, Yoshifumi; Mizushima, Tohru
• Is Part Of: Bioorganic & medicinal chemistry. Volume 27:Issue 15(2019)
• Page Start: 3339
• Page End: 3346
• Publication Date: 2019-08-01
• Subjects: aclidinium aclidinium bromide -- BALF bronchoalveolar lavage fluid -- CDI carbonyldiimidazole -- COPD chronic obstructive pulmonary disease -- FEV0.1 forced expiratory volume in 0.1 s -- FVC forced vital capacity -- glycopyrronium glycopyrronium bromide -- GST glutathione S-transferase -- hM2R human muscarinic M2 receptor -- hM3R human muscarinic M3 receptor -- HDAC2 Histone deacetylase 2 -- IFN interferon -- IL interleukin -- KC keratinocyte chemoattractant -- LABA long-acting β2-agonist -- LAMA long-acting muscarinic antagonist -- mepenzolate mepenzolate bromide -- MLI mean linear intercept -- [3H]NMS N-methyl-[3H]-scopolamine methylchloride -- PPE porcine pancreatic elastase -- QNB 3-quinuclidinyl benzilate -- ROS reactive oxygen species -- SOD superoxide dismutase -- tiotropium tiotropium bromide -- TNF tumor necrosis factor; Chemical modification -- Mepenzolate -- COPD -- Inflammatory -- Long-acting muscarinic antagonist; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2019.06.016
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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 modified5 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 (hM3 R). Compared to1 and5, ( 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.