RESUMEN
BACKGROUND AND PURPOSE: Angiotensin receptor-NEP inhibitor (ARNi), which includes an angiotensin receptor blocker (ARB) and a neprilysin inhibitor (NEPi), has been proven safe and effective for treating heart failure with reduced ejection fraction (HF-REF). S086 is a novel single-molecule ARNi that includes the molecular moieties of EXP3174 (the active metabolite of the ARB losartan) and sacubitril (a NEP inhibitor prodrug) in a 1:1 M ratio. We performed preclinical animal model studies to evaluate the efficacy of S086 in treating HF. EXPERIMENTAL APPROACH: Rat and dog models of myocardial ischemia-induced chronic heart failure were used in this research. PRINCIPAL RESULTS: The oral administration of S086 dose-dependently lowered the heart weight index, attenuated cardiac fibrosis, and improved left ventricular ejection fraction, shortening fraction, and cardiac output, without effects on hemodynamics in animal models of myocardial ischemia-induced chronic heart failure. A comparable protective effect to LCZ696 was observed for S086 at an equal molar dose in dog models. In addition, S086 was superior to LCZ696 since it significantly reversed the decrease in left ventricular posterior wall end-systolic thickness. CONCLUSION: This animal study suggests that S086 is effective in treating myocardial ischemia-induced chronic heart failure.
Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Insuficiencia Cardíaca/tratamiento farmacológico , Neprilisina/antagonistas & inhibidores , Inhibidores de Proteasas/farmacología , Administración Oral , Aminobutiratos/farmacología , Bloqueadores del Receptor Tipo 1 de Angiotensina II/administración & dosificación , Animales , Compuestos de Bifenilo , Cardiomegalia/etiología , Cardiomegalia/fisiopatología , Cardiomegalia/prevención & control , Enfermedad Crónica , Modelos Animales de Enfermedad , Perros , Combinación de Medicamentos , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/fisiopatología , Isquemia Miocárdica/complicaciones , Isquemia Miocárdica/fisiopatología , Inhibidores de Proteasas/administración & dosificación , Ratas Sprague-Dawley , Recuperación de la Función , Volumen Sistólico/efectos de los fármacos , Tetrazoles/farmacología , Valsartán , Función Ventricular Izquierda/efectos de los fármacosRESUMEN
Sitafloxacin is a newly developed fluoro-quinolone anti-bacterial drug. The crystal studied, C(19)H(18)ClF(2)N(3)O(3)·CH(3)OH, consists of one mol-ecule of sitafloxacin and one methanol solvent mol-ecule. The mol-ecule of sitafloxacin is a zwitterion with a protonated primary amine group and a deprotonated carboxylate group. The cyclopropane ring and the CO(2) group make dihedral angles of 79.5â (3) and 35.4â (4)°, respectively, with the fused ring system. The supra-molecular structure is defined by N-Hâ¯O and O-Hâ¯O hydrogen bonds.