Document Report Card

Basic Information

ID: ALA4385611

Journal: J Med Chem

Title: 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.

Authors: Barrett SD, Holt MC, Kramer JB, Germain B, Ho CS, Ciske FL, Kornilov A, Colombo JM, Uzieblo A, O'Malley JP, Owen TA, Stein AJ, Morano MI.

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.

CiteXplore: 30964292

DOI: 10.1021/acs.jmedchem.9b00336