Abstract
We describe the medicinal chemistry programme that led to the identification of the EP(1) receptor antagonist GSK269984A (8h). GSK269984A was designed to overcome development issues encountered with previous EP(1) antagonists such as GW848687X and was found to display excellent activity in preclinical models of inflammatory pain. However, upon cross species pharmacokinetic profiling, GSK269984A was predicted to have suboptimal human pharmacokinetic and was thus progressed to a human microdose study.
MeSH terms
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Analgesics / chemical synthesis*
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Analgesics / pharmacology
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Animals
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Central Nervous System / drug effects
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Chemistry, Pharmaceutical / methods*
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Drug Design
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Humans
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Hydrogen-Ion Concentration
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Inflammation / drug therapy*
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Inhibitory Concentration 50
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Models, Chemical
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Nicotinic Acids / chemical synthesis*
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Nicotinic Acids / pharmacology
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Pyridines / chemical synthesis*
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Pyridines / pharmacology
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Rats
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Receptors, Prostaglandin E / antagonists & inhibitors*
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Structure-Activity Relationship
Substances
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Analgesics
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Nicotinic Acids
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Pyridines
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Receptors, Prostaglandin E
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sodium 6-((5-chloro-2-(((4-chloro-2-fluorophenyl)methyl)oxy)phenyl)methyl)-2-pyridinecarboxylate