jm9b00336_si_004.pdb (496.19 kB)
Download fileDifluoromethylene 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
dataset
posted on 09.04.2019, 00:00 authored 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. MoranoA 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.