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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

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posted on 09.04.2019, 00:00 by Stephen D. Barrett, Melissa C. Holt, James B. Kramer, Bradlee Germain, Chi S. Ho, Fred L. Ciske, Andrei Kornilov, Joseph M. Colombo, Adam Uzieblo, James P. O’Malley, Thomas A. Owen, Adam J. Stein, Maria I. Morano
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.