Synthesis and in vitro sodium channel blocking activity evaluation of novel homochiral mexiletine analogs

Carocci, Alessia; Catalano, Alessia; Bruno, Claudio; Lentini, Giovanni; Franchini, Carlo; Bellis, Michela De; A, De Luca; Camerino, Diana Conte

doi:10.1002/chir.20741

Cited by 18 publications

(23 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Optical rotations were measured on a PerkinElmer (Norwalk, CT) Mod 341 spectropolarimeter; concentrations are expressed in g 100 mL −1 , and the cell length was 1 dm; thus, [ α ]

\frac{0pt}{20}

values are given in units of 10 −1 deg cm 2 g −1 . Chromatographic separations were performed on silica gel columns by flash chromatography (Kieselgel 60, 0.040–0.063 mm, Merck, Darmstadt, Germany) as elsewhere described . TLC analyses were performed on precoated silica gel on aluminum sheets (Kieselgel 60 F 254 , Merck).…”

Section: Methodsmentioning

confidence: 99%

Stereoselective Modulation of P‐Glycoprotein by Chiral Small Molecules

et al. 2015

Self Cite

View full text Add to dashboard Cite

Inhibition of drug efflux pumps such as P-glycoprotein (P-gp) is an approach toward combating multidrug resistance, which is a significant hurdle in current cancer treatments. To address this, N-substituted aryloxymethyl pyrrolidines were designed and synthesized in their homochiral forms in order to investigate the stereochemical requirements for the binding site of P-gp. Our study provides evidence that the chiral property of molecules could be a strategy for improving the capacity for interacting with P-gp, as the most active compounds of the series stereoselectively modulated this efflux pump. The naphthalene-1-yl analogue (R)-2-[(2,3-dichlorophenoxy)methyl]-1-(naphthalen-1-ylmethyl)pyrrolidine) [(R)-7 a] emerged foremost for its potency and stereoselectivity toward P-gp, with the S enantiomer being nearly inactive. The modulation of P-gp by (R)-7 a involved consumption of ATP, thus demonstrating that the compound behaves as a P-gp substrate.

show abstract

“…Optical rotations were measured on a PerkinElmer (Norwalk, CT) Mod 341 spectropolarimeter; concentrations are expressed in g 100 mL −1 , and the cell length was 1 dm; thus, [ α ]

\frac{0pt}{20}

Section: Methodsmentioning

confidence: 99%

Stereoselective Modulation of P‐Glycoprotein by Chiral Small Molecules

et al. 2015

Self Cite

View full text Add to dashboard Cite

show abstract

“…The compounds tested are shown in Fig. 1 (21). Chemical names and arbitrary abbreviated nomenclature are provided in the Additional Methods section, along with the composition of solutions with and without drugs.…”

Section: Solutions and Drugsmentioning

confidence: 99%

Combined Modifications of Mexiletine Pharmacophores for New Lead Blockers of Nav1.4 Channels

Bellis

Desaphy

et al. 2013

Biophysical Journal

Self Cite

View full text Add to dashboard Cite

Previously identified potent and/or use-dependent mexiletine (Mex) analogs were used as template for the rational design of new Na(v)-channel blockers. The effects of the novel analogs were tested on sodium currents of native myofibers. Data and molecular modeling show that increasing basicity and optimal alkyl chain length enhance use-dependent block. This was demonstrated by replacing the amino group with a more basic guanidine one while maintaining a proper distance between positive charge and aromatic ring (Me13) or with homologs having the chirality center nearby the amino group or the aromatic ring. Accordingly, a phenyl group on the asymmetric center in the homologated alkyl chain (Me12), leads to a further increase of use-dependent behavior versus the phenyl Mex derivative Me4. A fluorine atom in paraposition and one ortho-methyl group on the xylyloxy ring (Me15) increase potency and stereoselectivity versus Me4. Charge delocalization and greater flexibility of Me15 may increase its affinity for Tyr residues influencing steric drug interaction with the primary Phe residue of the binding site. Me12 and Me15 show limited selectivity against Na(v)-isoforms, possibly due to the highly conserved binding site on Na(v). To our knowledge, the new compounds are the most potent Mex-like Na(v) blockers obtained to date and deserve further investigation.

show abstract

“…Abnormalities in the expression and/or function of ion channels are responsible of many arrhythmias [1,2], thus, they represent one of the targets for antiarrhythmic therapy. Indeed, most of the existing antiarrhythmic agents, such as lidocaine, tocainide, and mexiletine [3,4] are ion channel blockers. Mexiletine (1a, Fig.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, antiarrhythmic activity, and toxicological evaluation of mexiletine analogues

Roselli

Carocci

Budriesi

et al. 2016

European Journal of Medicinal Chemistry

Self Cite

View full text Add to dashboard Cite

Four mexiletine analogues have been tested for their antiarrhythmic, inotropic, and chronotropic effects on isolated guinea pig heart tissues and to assess calcium antagonist activity, in comparison with the parent compound mexiletine. All analogues showed from moderate to high antiarrhythmic activity. In particular, three of them (1b,c,e) were more active and potent than the reference drug, while exhibiting only modest or no negative inotropic and chronotropic effects and vasorelaxant activity, thus showing high selectivity of action. All compounds showed no cytotoxicity and 1b,c,d did not impair motor coordination. All in, these new analogues exhibit an interesting cardiovascular profile and deserve further investigation.

show abstract

Synthesis and in vitro sodium channel blocking activity evaluation of novel homochiral mexiletine analogs

Cited by 18 publications

References 26 publications

Stereoselective Modulation of P‐Glycoprotein by Chiral Small Molecules

Stereoselective Modulation of P‐Glycoprotein by Chiral Small Molecules

Combined Modifications of Mexiletine Pharmacophores for New Lead Blockers of Nav1.4 Channels

Synthesis, antiarrhythmic activity, and toxicological evaluation of mexiletine analogues

Contact Info

Product

Resources

About