RESUMO
A chiral cobalt(III) complex (1e) was synthesized by the interaction of cobalt(II) acetate and ferrocenium hexafluorophosphate with a chiral dinuclear macrocyclic salen ligand that was derived from 1R,2R-(-)-1,2-diaminocyclohexane with trigol bis-aldehyde. A variety of epoxides and glycidyl ethers were suitable substrates for the reaction with water in the presence of chiral macrocyclic salen complex 1e at room temperature to afford chiral epoxides and diols by hydrolytic kinetic resolution (HKR). Excellent yields (47% with respect to the epoxides, 53% with respect to the diols) and high enantioselectivity (ee>99% for the epoxides, up to 96% for the diols) were achieved in 2.5-16 h. The Co(III) macrocyclic salen complex (1e) maintained its performance on a multigram scale and was expediently recycled a number of times. We further extended our study of chiral epoxides that were synthesized by using HKR to the synthesis of chiral drug molecules (R)-mexiletine and (S)-propranolol.
Assuntos
Cobalto/química , Mexiletina/química , Mexiletina/síntese química , Compostos Organometálicos/química , Compostos Organometálicos/síntese química , Propranolol/química , Propranolol/síntese química , Catálise , Cinética , Estrutura Molecular , EstereoisomerismoRESUMO
New chiral mexiletine analogs were synthesized in their optically active forms and evaluated in vitro as use-dependent blockers of skeletal muscle sodium channels. Tests carried out on sodium currents of single muscle fibers of Rana esculenta demonstrated that all of them exerted a higher use-dependent block than mexiletine. The most potent analog, (S)-3-(2,6-dimethylphenoxy)-1-phenylpropan-1-amine (S)-(5), was six-fold more potent than (R)-Mex in producing a tonic block. As observed with mexiletine, the newly synthesized compounds exhibit modest enantioselective behavior, that is more evident in 3-(2,6-dimethylphenoxy)butan-1-amine (3).
Assuntos
Mexiletina/síntese química , Mexiletina/farmacologia , Músculos/efeitos dos fármacos , Miotonia/tratamento farmacológico , Bloqueadores dos Canais de Sódio/farmacologia , Animais , Mexiletina/análogos & derivadosRESUMO
[2-(2-Aminopropoxy)-1,3-phenylene]dimethanol 1 and 4-(2-aminopropoxy)-3-(hydroxymethyl)-5-methylphenol 2, two dihydroxylated analogs of mexiletine - a well known class IB anti-arrhythmic drug - were synthesized and used as pharmacological tools to investigate the blocking-activity requirements of human skeletal muscle, voltage-gated sodium channel. The very low blocking activity shown by newly synthesized compounds corroborates the hypothesis that the presence of a phenolic group in the para-position to the aromatic moiety and/or benzylic hydroxyl groups on the aromatic moiety of local anesthetic-like drugs impairs either the transport to or the interaction with the binding site in the pore of Na(+) channels.
Assuntos
Antiarrítmicos/farmacologia , Mexiletina/análogos & derivados , Mexiletina/farmacologia , Bloqueadores dos Canais de Sódio/farmacologia , Canais de Sódio/metabolismo , Antiarrítmicos/síntese química , Antiarrítmicos/química , Sítios de Ligação , Linhagem Celular , Desenho de Fármacos , Humanos , Hidroxilação , Mexiletina/síntese química , Mexiletina/química , Músculo Esquelético/metabolismo , Bloqueadores dos Canais de Sódio/síntese química , Bloqueadores dos Canais de Sódio/química , Canais de Sódio/genética , Relação Estrutura-AtividadeRESUMO
Fragment-based lead discovery has been applied to urokinase-type plasminogen activator (uPA). The (R)-enantiomer of the orally active drug mexiletine 5 (a fragment hit from X-ray crystallographic screening) was the chemical starting point. Structure-aided design led to elaborated inhibitors that retained the key interactions of (R)-5 while gaining extra potency by simultaneously occupying neighboring regions of the active site. Subsequent optimization led to 15, a potent, selective, and orally bioavailable inhibitor of uPA.
Assuntos
Mexiletina/análogos & derivados , Mexiletina/síntese química , Ativador de Plasminogênio Tipo Uroquinase/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Cristalografia por Raios X , Mexiletina/química , Mexiletina/farmacologia , Modelos Moleculares , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Ativador de Plasminogênio Tipo Uroquinase/químicaRESUMO
A practical and efficient procedure for the enantioselective synthesis of mexiletine analogues with use of 10% of spiroborate ester 6 as chirality transfer agent is presented. A variety of mexiletine analogues were prepared in good yield with excellent enantioselectivities (91-97% ee) from readily available starting materials. The developed methodology was also successfully applied for the synthesis of novel beta-amino ethers containing thiophenyl and pyridyl fragments.
Assuntos
Antiarrítmicos/síntese química , Éteres/síntese química , Mexiletina/síntese química , Piridinas/química , Tiofenos/química , Boranos/química , Ésteres/química , Mexiletina/análogos & derivados , Modelos Químicos , EstereoisomerismoRESUMO
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.
Assuntos
Antiarrítmicos/farmacologia , Antiarrítmicos/toxicidade , Mexiletina/farmacologia , Mexiletina/toxicidade , Animais , Antiarrítmicos/síntese química , Antiarrítmicos/química , Aorta/efeitos dos fármacos , Aorta/fisiopatologia , Sobrevivência Celular/efeitos dos fármacos , Técnicas de Química Sintética , Cães , Cobaias , Átrios do Coração/efeitos dos fármacos , Átrios do Coração/fisiopatologia , Células Hep G2 , Humanos , Células Madin Darby de Rim Canino , Mexiletina/síntese química , Mexiletina/química , Relaxamento Muscular/efeitos dos fármacosRESUMO
Optically active mexiletine analogues were synthesized and evaluated in vitro as use-dependent blockers of skeletal muscle sodium channels. The mexiletine analogues were obtained by replacing either the methyl group on the stereogenic center of mexiletine [1-(2,6-dimethylphenoxy)propan-2-amine] with a phenyl group or modifying the phenoxy moiety (by removal of one or both of the methyl groups, or introducing a chlorine atom), or both. The voltage clamp recordings showed that, regardless of the substitution pattern of the aryloxy moiety, all the compounds bearing a phenyl group on the stereogenic center (3a-f) were more active than mexiletine both in tonic and phasic block. This observation was in contrast with what was observed for mexiletine, where the removal of both methyls from the aryloxy moiety caused a dramatic reduction of potency. The most potent congener, (R)-2-(2-methylphenoxy)-1-phenylethanamine [(R)-3b], was 27-fold more potent than (R)-mexiletine in producing a tonic block, i.e., the reduction of peak sodium current in resting conditions after application of the compound. (R)-3b maintained a use-dependent behavior, being 23-fold more potent in condition of high frequency of stimulation (phasic block). Despite what was observed with mexiletine, the stereoselectivity held in phasic block conditions. Stereoselectivity indexes were generally low, ranging from 1 to 4, but except for that of the 2,6-xylyloxy congener 3c, they were higher for the congeners bearing a phenyl ring on the stereogenic center than for mexiletine and its strictly related analogue 1-methyl-2-phenoxyethanamine (1). This finding was in agreement with Pfeiffer's rule. The introduction of a chlorine atom in the 4-position of the aryloxy moiety caused a reduction of potency and a reversal of stereoselectivity as well. On the basis of the model to date accepted for the sodium channel local anesthetic-like molecule receptor, some possible explanations of our observations will be proposed.
Assuntos
Ativação do Canal Iônico , Mexiletina/análogos & derivados , Mexiletina/síntese química , Fenetilaminas/síntese química , Éteres Fenílicos/síntese química , Bloqueadores dos Canais de Sódio/síntese química , Canais de Sódio/efeitos dos fármacos , Animais , Técnicas In Vitro , Mexiletina/farmacologia , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/fisiologia , Músculo Esquelético/ultraestrutura , Técnicas de Patch-Clamp , Fenetilaminas/farmacologia , Éteres Fenílicos/farmacologia , Rana esculenta , Bloqueadores dos Canais de Sódio/farmacologia , Canais de Sódio/fisiologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The optical isomers (-)-(S)- and (+)-(R)-3-(2, 6-dimethylphenoxy)-2-methyl-1-propanamine (Me2), homologues of the antiarrhythmic and antimyotonic drug mexiletine (Mex), were synthesized and assayed as new potential antimyotonic agents. As observed with Mex, Me2 exhibits an enantioselective behaviour. Tests carried out on sodium currents of single muscle fibres of Rana esculenta demonstrated that (-)-(S)- and (+)-(R)-Me2 were less potent than Mex in producing tonic block, but showed a higher use-dependent block. (-)-(S)-Me2 and (-)-(R)-Mex were also used to study the excitability of muscle fibres of myotonic ADR mice, a phenotype of a recessive form of low G(Cl) myotonia. (-)-(S)-Me2 reduced spontaneous discharges and after discharges better than (-)-(R)-Mex in agreement with the use-dependent block of sodium currents.
Assuntos
Mexiletina/análogos & derivados , Mexiletina/química , Músculo Esquelético/fisiopatologia , Miotonia/tratamento farmacológico , Bloqueadores dos Canais de Sódio , Animais , Antiarrítmicos/química , Condutividade Elétrica , Mexiletina/síntese química , Mexiletina/farmacologia , Mexiletina/uso terapêutico , Camundongos , Camundongos Mutantes , Estrutura Molecular , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/fisiologia , Músculo Esquelético/efeitos dos fármacos , Miotonia/fisiopatologia , Rana esculenta , EstereoisomerismoRESUMO
Nine new compounds were synthesized and tested for their alpha-adrenoceptor affinity and antihypertensive activity together with 5 other previously reported compounds. Compounds I, IIa, IIb and IIIa showed high alpha-adrenoceptor affinity and strong antihypertensive activity.
Assuntos
Anti-Hipertensivos , Pressão Sanguínea/efeitos dos fármacos , Etilaminas/síntese química , Mexiletina/análogos & derivados , Animais , Etilaminas/farmacologia , Mexiletina/síntese química , Mexiletina/farmacologia , Ratos , Receptores Adrenérgicos alfa/metabolismoRESUMO
Mexiletine is a very well-known class IB antiarrhythmic drug, whose enantiomers differ in both pharmacodynamic and pharmacokinetic properties, the (R)-isomer being the eutomer on experimental arrhythmias and in binding studies on cardiac voltage-gated sodium channels. meta-Hydroxymexiletine (MHM) is a minor metabolite of mexiletine, which has demonstrated to be more potent than the parent compound. Herein we report the synthesis and biological evaluation of MHM enantiomers for their potential antiarrhythmic activity. The same stereoselectivity pattern observed for mexiletine was found for MHM: the (R)-enantiomer of MHM was the eutomer on ac-arrhythmia also showing a negative inotropism higher than the one displayed by mexiletine and, at the same time, a decreased vasorelaxant activity on guinea-pig left atrium and guinea-pig ileum longitudinal smooth muscle.
Assuntos
Antiarrítmicos/farmacologia , Fibrilação Atrial/tratamento farmacológico , Átrios do Coração/efeitos dos fármacos , Mexiletina/análogos & derivados , Músculo Liso/efeitos dos fármacos , Animais , Antiarrítmicos/síntese química , Antiarrítmicos/química , Feminino , Cobaias , Átrios do Coração/metabolismo , Átrios do Coração/patologia , Mexiletina/síntese química , Mexiletina/química , Mexiletina/farmacologia , Estrutura Molecular , Músculo Liso/metabolismo , Músculo Liso/patologia , EstereoisomerismoRESUMO
m-Hydroxymexiletine (MHM) is a metabolite of mexiletine, a well known class IB anti-arrhythmic drug, which presents almost twice the activity of the parent compound on cardiac voltage-gated sodium channels. Given the different activity of mexiletine enantiomers on sodium currents (being the R-isomer the eutomer), it is conceivable that (R)- and(S)-MHM could differ in pharmacodynamic and pharmacokinetic properties, too. Herein we report the efficient synthesis of MHM enantiomers that could represent useful tools for further investigations on stereospecific requirements of the voltage-gated sodium channel binding site. MHM enantiomers and all the homochiral intermediates were fully characterized. The ee values for (R)- and (S)-MHM were >99%, as assessed by capillary electrophoresis using ß-cyclodextrin sulfated sodium salt as a chiral selector.
Assuntos
Eletroforese Capilar/métodos , Mexiletina/análogos & derivados , Bloqueadores do Canal de Sódio Disparado por Voltagem/síntese química , Mexiletina/síntese química , Mexiletina/química , Estereoisomerismo , Sulfatos/química , Bloqueadores do Canal de Sódio Disparado por Voltagem/química , beta-Ciclodextrinas/químicaRESUMO
m-Hydroxymexiletine (MHM), a minor metabolite of the class IB anti-arrhythmic drug mexiletine, is about two fold more potent than the parent compound on human cardiac voltage-gated sodium channels (hNav1.5), and equipotent to mexiletine on human skeletal-muscle voltage-gated sodium channels (hNav1.4). Herein, an alternative and simplified synthesis of this promising compound has been accomplished. This route, as well as being more efficient, has the advantage, over the first, to avoid the use of oxidizing agents, such as the meta-chloroperoxybenzoic acid.
Assuntos
Antiarrítmicos/síntese química , Mexiletina/análogos & derivados , Bloqueadores do Canal de Sódio Disparado por Voltagem/síntese química , Antiarrítmicos/farmacologia , Células HEK293 , Humanos , Mexiletina/síntese química , Mexiletina/farmacologia , Canal de Sódio Disparado por Voltagem NAV1.4/efeitos dos fármacos , Canal de Sódio Disparado por Voltagem NAV1.5/efeitos dos fármacos , Estereoisomerismo , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologiaRESUMO
The first synthesis of m-hydroxymexiletine (MHM) has been accomplished. MHM displayed hNav1.5 sodium channel blocking activity, and tests indicate it to be â¼2-fold more potent than the parent mexiletine and to have more favorable toxicological properties than mexiletine. Thus, MHM and possible related prodrugs might be studied as agents for the treatment of arrhythmias, neuropathic pain, and myotonias in substitution of mexiletine (metabolite switch), which has turned out to be tainted with common toxicity.
Assuntos
Antiarrítmicos/síntese química , Mexiletina/análogos & derivados , Mexiletina/metabolismo , Canais de Sódio/fisiologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Antiarrítmicos/metabolismo , Antiarrítmicos/toxicidade , Aorta/efeitos dos fármacos , Aorta/fisiologia , Ataxia/induzido quimicamente , Barreira Hematoencefálica/metabolismo , Células CACO-2 , Cobaias , Células HEK293 , Coração/efeitos dos fármacos , Coração/fisiologia , Frequência Cardíaca/efeitos dos fármacos , Humanos , Ativação do Canal Iônico , Mexiletina/síntese química , Mexiletina/toxicidade , Camundongos , Canal de Sódio Disparado por Voltagem NAV1.5 , Permeabilidade , Estereoisomerismo , Vasodilatadores/síntese química , Vasodilatadores/toxicidadeRESUMO
(S)- as well as (R)-mexiletine [1-(2,6-dimethylphenoxy)-2-propanamine], a chiral orally effective antiarrhythmic agent, was prepared by deracemization starting from the commercially available racemic amine using omega-transaminases in up to >99% ee and conversion with 97% isolated yield by a one-pot two-step procedure. The absolute configuration could be easily switched to the other enantiomer, just by switching the order of the applied transaminases. The cosubstrate pyruvate needed in the first oxidative step was recycled by using an amino acid oxidase.
Assuntos
Aminoácido Oxirredutases/metabolismo , Antiarrítmicos/síntese química , Mexiletina/síntese química , Transaminases/metabolismo , Aminas/química , Antiarrítmicos/química , Catálise , Mexiletina/química , Estrutura Molecular , Estereoisomerismo , Transaminases/químicaRESUMO
The title compounds, 1a and 1b, have been synthesized in a three-step sequence starting from (-)-(S) and (+)-(R)-propylene oxide, respectively, in acceptable overall yields. The enantiomeric excess values for 1a and 1b were 96% and 93% respectively, as assessed by HPLC analysis on a chiral stationary phase of the corresponding N-acetyl derivatives. The synthetic route herein presented may represent a facile entry to highly enriched mexiletine enantiomers, alternative to those previously reported in the literature.
Assuntos
Antiarrítmicos/síntese química , Mexiletina/síntese química , Mexiletina/química , EstereoisomerismoRESUMO
Both enantiomers of "para-hydroxymexiletine" (PHM), one of the main metabolites of mexiletine, were synthesized and fully characterized. Properties of (R)- and (S)-PHM, in terms of blocking potency and stereoselectivity on frog skeletal muscle Na(+) channels, were evaluated. The presence of a hydroxy group on the aryloxy moiety in the 4-position, as in PHM, reduced potency with respect to mexiletine in reducing I(Na max). However, PHM showed clear use-dependent behavior similar to that of mexiletine and, in contrast with what is observed with the parent compound, maintained its stereoselectivity during the use-dependent block. Chirality 16:72-78, 2004.