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

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

doi:10.1021/acs.jmedchem.9b00336

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

J Med Chem. 2019 May 9;62(9):4731-4741. doi: 10.1021/acs.jmedchem.9b00336. Epub 2019 Apr 26.

Authors

Affiliations

¹ Cayman Chemical Company, Inc. , 1180 East Ellsworth Road , Ann Arbor , Michigan 48108 , United States.
² Myometrics, LLC , 216 Howard Street , New London , Connecticut 06320 , United States.
³ Ramapo College of New Jersey , 505 Ramapo Valley Road , Mahwah , New Jersey 07430 , United States.

PMID: 30964292
DOI: 10.1021/acs.jmedchem.9b00336

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

Alprostadil / analogs & derivatives*
Alprostadil / metabolism
Alprostadil / pharmacology*
Animals
Binding Sites
CHO Cells
Caco-2 Cells
Cricetulus
Heptanoic Acids / pharmacology*
Humans
Lactams / chemical synthesis
Lactams / metabolism
Lactams / pharmacology*
Models, Chemical
Molecular Docking Simulation
Molecular Structure
Pyrrolidines / pharmacology*
Quantum Theory
Receptors, Prostaglandin E, EP3 Subtype / chemistry
Receptors, Prostaglandin E, EP3 Subtype / metabolism
Receptors, Prostaglandin E, EP4 Subtype / agonists*
Receptors, Prostaglandin E, EP4 Subtype / chemistry
Receptors, Prostaglandin E, EP4 Subtype / metabolism

Substances

Heptanoic Acids
KMN-159
Lactams
Pyrrolidines
Receptors, Prostaglandin E, EP3 Subtype
Receptors, Prostaglandin E, EP4 Subtype
Alprostadil