RESUMEN
Soluble guanylate cyclase (sGC), the endogenous receptor for nitric oxide (NO), has been implicated in several diseases associated with oxidative stress. In a pathological oxidative environment, the heme group of sGC can be oxidized becoming unresponsive to NO leading to a loss in the ability to catalyze the production of cGMP. Recently a dysfunctional sGC/NO/cGMP pathway has been implicated in contributing to elevated intraocular pressure associated with glaucoma. Herein we describe the discovery of molecules specifically designed for topical ocular administration, which can activate oxidized sGC restoring the ability to catalyze the production of cGMP. These efforts culminated in the identification of compound (+)-23, which robustly lowers intraocular pressure in a cynomolgus model of elevated intraocular pressure over 24 h after a single topical ocular drop and has been selected for clinical evaluation.
Asunto(s)
Activadores de Enzimas/síntesis química , Activadores de Enzimas/uso terapéutico , Glaucoma/tratamiento farmacológico , Guanilil Ciclasa Soluble/efectos de los fármacos , Administración Oftálmica , Administración Tópica , Animales , Células CHO , Cricetinae , Cricetulus , GMP Cíclico/biosíntesis , Descubrimiento de Drogas , Activadores de Enzimas/administración & dosificación , Humanos , Presión Intraocular/efectos de los fármacos , Macaca fascicularis , Soluciones Oftálmicas , Oxidación-Reducción , ConejosRESUMEN
The ATPase subunit of DNA gyrase B is an attractive antibacterial target due to high conservation across bacteria and the essential role it plays in DNA replication. A novel class of pyrazolopyridone inhibitors was discovered by optimizing a fragment screening hit scaffold using structure guided design. These inhibitors show potent Gram-positive antibacterial activity and low resistance incidence against clinically important pathogens.