Abstract
To identify topically effective EP4 agonists and EP2/EP4 dual agonists with excellent subtype selectivity, further optimization of the 16-phenyl ω-chain moiety of the γ-lactam 5-thia prostaglandin E analog and the 2-mercaptothiazole-4-carboxylic acid analog were undertaken. Rat in vivo evaluation of these newly identified compounds as their poly (lactide-co-glycolide) microsphere formulation, from which sustained release of the test compound is possible, led us to discover compounds that showed efficacy in a rat bone fracture healing model after its topical administration without serious influence on blood pressure and heart rate. A structure-activity relationship study is also presented.
Copyright © 2012 Elsevier Ltd. All rights reserved.
MeSH terms
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Administration, Topical
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Animals
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Blood Pressure / drug effects
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CHO Cells
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Cricetinae
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Delayed-Action Preparations / administration & dosage
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Delayed-Action Preparations / chemistry
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Dinoprostone / chemistry
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Drug Evaluation, Preclinical / methods
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Fracture Healing / drug effects
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Heart Rate / drug effects
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Lactams / administration & dosage
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Lactams / chemical synthesis*
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Lactams / pharmacology*
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Male
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Mice
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Microspheres
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Molecular Structure
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Polyglactin 910 / administration & dosage
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Polyglactin 910 / chemistry
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Prostaglandins E, Synthetic / chemical synthesis*
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Prostaglandins E, Synthetic / pharmacology*
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Rats
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Rats, Sprague-Dawley
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Receptors, Prostaglandin E, EP2 Subtype / agonists*
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Receptors, Prostaglandin E, EP4 Subtype / agonists*
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Structure-Activity Relationship
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Thiazolidines / chemistry
Substances
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2-mercaptothiazole-4-carboxylic acid
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Delayed-Action Preparations
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Lactams
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Prostaglandins E, Synthetic
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Receptors, Prostaglandin E, EP2 Subtype
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Receptors, Prostaglandin E, EP4 Subtype
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Thiazolidines
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Polyglactin 910
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Dinoprostone