Discovery of Nitro-azolo[1,5- a ]pyrimidines with Anti-Inflammatory and Protective Activity against LPS-Induced Acute Lung Injury.
Alexander A SpasovVadim A KosolapovDenis A BabkovVladlen KlochkovElena SokolovaMikhail MiroshnikovAlexander BorisovYulia VelikorodnayaAlexey SmirnovKonstantin V SavateevVictor FedotovSvetlana KotovskayaVladimir RusinovPublished in: Pharmaceuticals (Basel, Switzerland) (2022)
Acute lung injury remains a challenging clinical condition, necessitating the development of novel, safe and efficient treatments. The prevention of macrophage M1-polarization is a viable venue to tackle excessive inflammation. We performed a phenotypic screening campaign to identify azolopyrimidine compounds that effectively inhibit LPS-induced NO synthesis and interleukin 6 (IL-6) secretion. We identified lead compound 9g that inhibits IL-6 secretion with IC 50 of 3.72 µM without apparent cytotoxicity and with minimal suppression of macrophage phagocytosis in contrast to dexamethasone. In a mouse model of LPS-induced acute lung injury, 30 mg/kg i.p. 9g ameliorated anxiety-like behavior, inhibited IL-6 release, and limited neutrophil infiltration and pulmonary edema. A histological study confirmed the protective activity of 9g . Treatment with compound 9g prevented the migration of CD68 + macrophages and the incidence of hemorrhage. Hence, we have identified a promising pharmacological approach for the treatment of acute lung injury that may hold promise for the development of novel drugs against cytokine-mediated complications of bacterial and viral infections.
Keyphrases
- lps induced
- inflammatory response
- mouse model
- lipopolysaccharide induced
- anti inflammatory
- adipose tissue
- sars cov
- magnetic resonance
- pulmonary hypertension
- magnetic resonance imaging
- small molecule
- low dose
- body mass index
- big data
- depressive symptoms
- drug induced
- high throughput
- replacement therapy
- contrast enhanced
- combination therapy
- weight gain
- artificial intelligence
- nk cells