Discovery of Potent and Orally Active Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) Inhibitors as a Potential Therapy for Diabetic Macular Edema
| Autor: | Kai Wang, Quanxin Ma, Minli Chen, Yiping Wang, Mingguang Mo, Xinde Chen, Lili Du, Wenwei Xu, Jianhua Shen |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male Stereochemistry Phospholipase A2 Inhibitors Diabetic macular edema Pharmacology Macular Edema Retina Diabetes Mellitus Experimental Rats Sprague-Dawley 03 medical and health sciences chemistry.chemical_compound Mice Structure-Activity Relationship Phospholipase A2 Pharmacokinetics In vivo Drug Discovery Animals Humans Pyrimidone Dosing Diabetic Retinopathy biology Lipoprotein-associated phospholipase A2 Cell Membrane In vitro Rats 030104 developmental biology chemistry Liver 1-Alkyl-2-acetylglycerophosphocholine Esterase biology.protein Molecular Medicine lipids (amino acids peptides and proteins) Caco-2 Cells |
| Zdroj: | Journal of medicinal chemistry. 59(6) |
| ISSN: | 1520-4804 |
| Popis: | Lipoprotein-associated phospholipase A2 (Lp-PLA2) is considered to be a promising therapeutic target for several inflammation-associated diseases. Herein, we describe the discovery of a series of pyrimidone derivatives as Lp-PLA2 inhibitors. Systematic structural modifications led to the identification of several pyrimidone compounds with promising in vitro inhibitory potency and pharmacokinetic properties. Compound 14c, selected for in vivo evaluation, demonstrated decent pharmacokinetic profiles and robust inhibitory potency against Lp-PLA2 in Sprague–Dawley (SD) rats. Furthermore, 14c significantly inhibited retinal thickening in STZ-induced diabetic SD rats as a model of diabetic macular edema (DME) after oral dosing for 4 weeks. Taken together, these results suggested that 14c can serve as a valuable lead in the search for new Lp-PLA2 inhibitors for prevention and/or treatment of DME. |
| Databáze: | OpenAIRE |
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