JM25-1, a Lidocaine Analog Combining Airway Relaxant and Antiinflammatory Properties

Abstract

Background Inhaled lidocaine antagonized bronchospasm in animal models and patients, but adverse effects limited its efficacy. This study evaluated the antibronchospasm potential of the analog JM25-1, exploring in vitro mechanisms and translation to an animal model. Methods The effectiveness of JM25-1 was assessed in GH3 cells, rat tracheal rings, mouse lymphocytes, and human eosinophil systems in vitro, assessing changes in Na+ current, contraction, proliferation, and survival, respectively. Lung function and inflammatory changes were studied in ovalbumin-sensitized mice. Results The efficacy of JM25-1 was higher than lidocaine in inhibiting carbachol-induced and calcium-induced tracheal contractions (maximum effect inhibition at 1 mM [%]: 67 ± 10 [JM25-1] vs. 41 ± 11 [lidocaine] [P < 0.001] for carbachol; 100 ± 3 [JM25-1] vs. 36 ± 26 [lidocaine] [P < 0.001] for Ca2+; mean ± SD; n = 9 each) but lower in Na+ current (50% inhibitory concentration = 151.5, n = 8 vs. 0.2 mM; n = 5; P < 0.001). JM25-1 also inhibited eosinophil survival (dead cells [%]: 65 ± 6; n = 4; P < 0.001 at 1 mM) and lymphocyte proliferation (cells in phase S + G2 [%]: 94 ± 10; n = 6; P < 0.001) at 0.6 mM. Aerosolized JM25-1 (1%) decreased lung eosinophil numbers from 13.2 ± 2.4 to 1.7 ± 0.7 × 104/μm2 (n = 6; P < 0.001) and neutrophils from 1.9 ± 0.4 to 0.2 ± 0.1 × 104/μm2 (n = 7; P < 0.001). Other parameters, including airway hyperreactivity, cytokines, mucus, and extracellular matrix deposition, were also sensitive to aerosolized JM25-1. Conclusion These findings highlight the potential of JM25-1, emphasizing its putative value in drug development for clinical conditions where there is bronchospasm.

Effect of Proparacaine in a Mouse Model of Allergic Rhinitis

“…We found that intranasal administration of PPC inhibited goblet cell infiltration in the nasal mucosa of mouse model of allergic rhinitis. This finding was in concordance with a recent study which found that a lidocaine analog significantly inhibited OVAinduced mucus secretion in mice [18]. A different study found that topical application of lidocaine inhibited mucous secretion [19].…”

15-Deoxy-Delta-12,14-Prostaglandin J2 Inhibits Lung Inflammation and Remodeling in Distinct Murine Models of Asthma

“…Commercial enzyme immunosorbent assay (ELISA) kits were used for the measurement of cytokine and chemokine proteins in whole-lung homogenates and cell-free supernatants as reported (38). Briefly, lung tissue was homogenized on ice using a tissue homogeneizer (Omni International, Kennesaw, GA, USA) in 1 ml PBS containing 0.05% Triton X-100 and a protease inhibitor cocktail (Hoffmann-La Roche, Basel, Switzerland).…”

Nickel‐Catalyzed Amide Bond Formation from Methyl Esters

“…[9] Here-in, we present how transition metal-catalyzed ester activation can be exploited to couple avery broad range of methyl esters with amines,a voiding the substantial scope limitations of existing systems.Asimple Ni 0 catalyst is used, providing high functional group tolerance and producing methanol as the only stoichiometric by-product. Most importantly,n on-nucleophilic aniline derivatives,w hich typically require pre-treatment with aggressive base prior to reaction with esters,c ould be used without any modification of the conditions (13)(14)(15)(16)(17)(18). We began by investigating the reaction of methyl benzoate with aselection of metals,ligands,and nucleophiles that had proven effective in previous catalytic coupling reactions that require cleavage of strong C À Obonds ( Figure S1).…”

“…[12] With ester activation, methyl chloroacetate can instead be used to first substitute at the a-carbon and then diversify the amide component by Ni-catalyzed coupling.This strategy was used to more efficiently access lidocaine derivatives 46-48 and JM25-1, [13] ar ecently discovered potential bronchospasm therapeutic (Scheme 4b). The orthogonality of using am etal to activate esters was investigated via reactions with methyl 4-fluorobenzoate 41.T raditional S N Ar reactions were achieved when using DMSO as as olvent (42, 43), while amide bond formation occurred selectively in toluene with the Ni catalyst (44, 45)( Scheme 4a).…”

“…Acompetition experiment between phenylethylamine and dibutylamine demonstrated high chemoselecitivity,p roviding the secondary amide 8 in 88 %y ield. Most importantly,n on-nucleophilic aniline derivatives,w hich typically require pre-treatment with aggressive base prior to reaction with esters,c ould be used without any modification of the conditions (13)(14)(15)(16)(17)(18). Furthermore,ethyl benzoate could also be used to make benzanilide 13,d emonstrating that the reaction is not limited to methyl esters.…”