Abstract
Inhibition of lipoprotein-associated phospholipase A2 (Lp-PLA2) has been suggested to be a promising therapeutic strategy for several inflammation-associated diseases, including atherosclerosis, Alzheimer's disease, and diabetic macular edema. Herein, we report the discovery of a novel series of Lp-PLA2 inhibitors constructed on an imidazo[1,2-a]pyrimidine scaffold through a conformational restriction strategy. Structure-activity relationship (SAR) analysis resulted in the identification of several compounds with high potency in vitro and good metabolic stability in liver S9 fractions. Compounds 7c and 14b selected for further exploration in vivo demonstrated excellent pharmacokinetic profiles and exhibited significant inhibitory efficacy in SD rats upon oral dosing.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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1-Alkyl-2-acetylglycerophosphocholine Esterase / antagonists & inhibitors*
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1-Alkyl-2-acetylglycerophosphocholine Esterase / metabolism
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Administration, Oral
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Animals
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Enzyme Inhibitors / administration & dosage
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / pharmacokinetics
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Enzyme Inhibitors / pharmacology*
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Humans
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Imidazoles / administration & dosage
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Imidazoles / chemistry*
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Imidazoles / pharmacokinetics
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Imidazoles / pharmacology*
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Male
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Mice
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Pyrimidines / administration & dosage
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Pyrimidines / chemistry*
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Pyrimidines / pharmacokinetics
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Pyrimidines / pharmacology*
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Rats
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Rats, Sprague-Dawley
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Structure-Activity Relationship
Substances
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Enzyme Inhibitors
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Imidazoles
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Pyrimidines
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imidazo(1,2-c)pyrimidine
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1-Alkyl-2-acetylglycerophosphocholine Esterase