RESUMEN
The paper describes the Suzuki cross-coupling of a variety of N and C-3 substituted 5-bromoindazoles with N-Boc-2-pyrrole and 2-thiopheneboronic acids. The reactions, performed in the presence of K(2)CO(3), dimethoxyethane and Pd(dppf)Cl(2) as catalyst, gave the corresponding adducts in good yields. The methodology allows the facile production of indazole-based heteroaryl compounds, a unique architectural motif that is ubiquitous in biologically active molecules.
Asunto(s)
Indazoles/síntesis química , Pirroles/química , Tiofenos/química , Catálisis , Indazoles/químicaRESUMEN
Glaucoma affects millions of people worldwide and causes optic nerve damage and blindness. The elevation of the intraocular pressure (IOP) is the main risk factor associated with this pathology, and decreasing IOP is the key therapeutic target of current pharmacological treatments. As potential ocular hypotensive agents, we studied compounds that act on two receptors (serotonin 2A and adrenergic α1 ) linked to the regulation of aqueous humour dynamics. Herein we describe the design, synthesis, and pharmacological profiling of a series of novel bicyclic and tricyclic N2-alkyl-indazole-amide derivatives. This study identified a 3,4-dihydropyrazino[1,2-b]indazol-1(2H)-one derivative with potent serotonin 2A receptor antagonism, >100-fold selectivity over other serotonin subtype receptors, and high affinity for the α1 receptor. Moreover, upon local administration, this compound showed superior ocular hypotensive action inâ vivo relative to the clinically used reference compound timolol.
Asunto(s)
Indazoles/uso terapéutico , Hipertensión Ocular/tratamiento farmacológico , Pirazinas/uso terapéutico , Receptor de Serotonina 5-HT2A/efectos de los fármacos , Receptores Adrenérgicos alfa 1/efectos de los fármacos , Animales , Descubrimiento de Drogas , Indazoles/química , Indazoles/farmacología , Presión Intraocular/efectos de los fármacos , Pirazinas/química , Pirazinas/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
The synthesis and the characterization of three new naproxen decorated polymers are described. A versatile and general approach is employed to link the drug to polymers, affording the derivatives with a very high degree of purity. The release of the drug from the conjugates proved to be exceptionally slow, even in acidic aqueous media, and the kinetic of the process seems to be triggered by their solubility in water. On the other hand, the interesting outcome of the first ex vivo drug release experiments on human blood samples makes this preliminary study valuable for future investigations on the use of these polymeric prodrugs in in vivo treatment of inflammatory states.