RESUMEN
Conceptual design and modification of urea moiety in chemotype PF-3845/04457845, the bench marking irreversible inhibitor of fatty acid amide hydrolase (FAAH), led to discovery of a novel nicotinamide-based lead 12a having reversible mechanism of action. Focused SAR around the pyridine heterocycle (Ar) in 12a (Tables 1 and 2) resulted into four shortlisted compounds, (-)-12a, (-)-12i, (-)-12l-m. The required (-)-enantiomers were obtained via diastereomeric resolution of a novel chiral dissymmetric intermediate 15. Based on comparative profile of FAAH potency, metabolic stability in liver microsome, liability of inhibiting major hCYP450 isoforms, rat PK, and brain penetration ability, two SAR optimized compounds, (-)-12l and (-)-12m, were selected for efficacy study in rat model of chemotherapy-induced peripheral neuropathy (CIPN). Both the compounds exhibited dose related antihyperalgesic effects, when treated with 3-30â¯mg/kg po for 7â¯days. The effects at 30â¯mg/kg are comparable to that of PF-04457845 (10â¯mg/kg) and Tramadol (40â¯mg/kg).
Asunto(s)
Amidohidrolasas/antagonistas & inhibidores , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Hipoglucemiantes/farmacología , Neuralgia/tratamiento farmacológico , Amidohidrolasas/metabolismo , Animales , Antineoplásicos/efectos adversos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Hipoglucemiantes/síntesis química , Hipoglucemiantes/química , Estructura Molecular , Neuralgia/metabolismo , Ratas , Relación Estructura-ActividadRESUMEN
A novel series of acylides 4 were designed to overcome antibacterial resistance and evaluated for in vitro and in vivo activity. This series of acylides was designed from clarithromycin by changing the substitution on the desosamine nitrogen, followed by conversion to 3-O-acyl and 11,12-carbamate. These compounds showed significantly potent antibacterial activity against not only Gram-positive pathogens, including macrolide-lincosamide-streptogramin B (MLS(B))-resistant and efflux-resistant strains, but also Gram-negative pathogens such as Haemophilus influenzae. These acylides also showed better activity against telithromycin resistant Streptococcus pneumoniae strains.
Asunto(s)
Antibacterianos/síntesis química , Química Farmacéutica/métodos , Infecciones del Sistema Respiratorio/tratamiento farmacológico , Claritromicina/análogos & derivados , Claritromicina/química , Diseño de Fármacos , Farmacorresistencia Bacteriana , Haemophilus influenzae/metabolismo , Humanos , Cetólidos/química , Cetólidos/farmacología , Pruebas de Sensibilidad Microbiana , Modelos Químicos , Nitrógeno/química , Streptococcus pneumoniae/metabolismoRESUMEN
An efficient synthesis of potent molluscicidal agent cyanolide A, a glycosidic 16-membered macrolide, starting from D-(-)-pantolactone is reported. Highly stereoselective aldol, oxa-Michael addition, and Yamaguchi macrolactonization are the key steps in the present synthesis.
