Abstract
A series of small-molecule full agonists of the prostaglandin E2 type 4 (EP4) receptor have been generated and evaluated for binding affinity and cellular potency. KMN-80 and its gem-difluoro analog KMN-159 possess high selectivity relative to other prostanoid receptors. Difluoro substitution is positioned alpha to the lactam ring carbonyl and results in KMN-159's fivefold increase in potency versus KMN-80. The two analogs exhibit electronic and conformational variations, including altered nitrogen hybridization and lactam ring puckering, that may drive the observed difluoro-associated increased potency within this four-compound series.
MeSH terms
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Alprostadil / analogs & derivatives*
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Alprostadil / metabolism
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Alprostadil / pharmacology*
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Animals
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Binding Sites
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CHO Cells
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Caco-2 Cells
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Cricetulus
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Heptanoic Acids / pharmacology*
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Humans
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Lactams / chemical synthesis
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Lactams / metabolism
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Lactams / pharmacology*
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Models, Chemical
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Molecular Docking Simulation
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Molecular Structure
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Pyrrolidines / pharmacology*
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Quantum Theory
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Receptors, Prostaglandin E, EP3 Subtype / chemistry
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Receptors, Prostaglandin E, EP3 Subtype / metabolism
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Receptors, Prostaglandin E, EP4 Subtype / agonists*
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Receptors, Prostaglandin E, EP4 Subtype / chemistry
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Receptors, Prostaglandin E, EP4 Subtype / metabolism
Substances
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Heptanoic Acids
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KMN-159
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Lactams
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Pyrrolidines
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Receptors, Prostaglandin E, EP3 Subtype
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Receptors, Prostaglandin E, EP4 Subtype
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Alprostadil