Difluoromethylene at the γ-Lactam α-Position Improves 11-Deoxy-8-aza-PGE₁ Series EP₄ Receptor Binding and Activity: 11-Deoxy-10,10-difluoro-8-aza-PGE₁ Analog (KMN-159) as a Potent EP₄ Agonist

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...