RESUMO
New inhibitors of palmitoyl-CoA oxidation are based on the introduction of nitrogen heterocycles in the 'Western Portion' of the molecule. SAR studies led to the discovery of CVT-4325 (shown), a potent FOXi (IC50=380 nM rat mitochondria) with favorable PK properties (F=93%, t(1/2)=13.6h, dog).
Assuntos
Antioxidantes/farmacologia , Antioxidantes/farmacocinética , Ácidos Graxos/metabolismo , Oxidiazóis/farmacologia , Oxidiazóis/farmacocinética , Palmitoil Coenzima A/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Cães , Ácidos Graxos/química , Humanos , Conformação Molecular , Oxirredução/efeitos dos fármacos , Palmitoil Coenzima A/metabolismo , Ratos , Relação Estrutura-AtividadeRESUMO
Atrial fibrillation (AF) is the most commonly encountered sustained clinical arrhythmia with an estimated 2.3 million cases in the US (2001). A(1) adenosine receptor agonists can slow the electrical impulse propagation through the atrioventricular (AV) node (i.e., negative dromotropic effect) resulting in prolongation of the stimulus-to-His bundle (S-H) interval to potentially reduce ventricular rate. Compounds that are full agonists of the A(1) adenosine receptor can cause high grade AV block. Therefore, it is envisioned that a compound that is a partial agonist of the A(1) adenosine receptor could avoid this deleterious effect. 5(') Phenyl sulfides (e.g., 17, EC(50)=1.26 microM) and phenyl ethers (e.g., 28, EC(50)=0.2 microM) are partial agonists with respect to their AV nodal effects in guinea pig isolated hearts. Additional affinity, GTPgammaS binding data suggesting partial activity of the A(1) adenosine receptor, and PK results for 5(') modified adenosine derivatives are shown.
Assuntos
Agonistas do Receptor A1 de Adenosina , Antiarrítmicos/síntese química , Éteres/síntese química , Hidrocarbonetos Aromáticos/química , Sulfetos/síntese química , Adenosina/metabolismo , Animais , Antiarrítmicos/farmacocinética , Arritmias Cardíacas/tratamento farmacológico , Nó Atrioventricular/efeitos dos fármacos , Nó Atrioventricular/metabolismo , Sítios de Ligação , Fascículo Atrioventricular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Éteres/farmacocinética , Cobaias , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Receptor A1 de Adenosina/metabolismo , Relação Estrutura-Atividade , Sulfetos/farmacocinéticaRESUMO
New inhibitors of palmitoylCoA oxidation were synthesized based on a structurally novel lead, CVT-3501 (1). Investigation of structure-activity relationships was conducted with respect to potency of inhibition of cardiac mitochondrial palmitoylCoA oxidation and metabolic stability. Potent and metabolically stable analogues 33, 42, and 43 were evaluated in vitro for cytochrome P450 inhibition and potentially adverse electrophysiological effects. Compound 33 was also found to have favorable pharmacokinetic properties in rat.