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

Abstract

A series of small-molecule full agonists of the prostaglandin E 2 type 4 (EP 4 ) 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 difluoroassociated increased potency within this four-compound series.

Enantiomeric Resolution and Absolute Configuration of a Chiral δ-Lactam, Useful Intermediate for the Synthesis of Bioactive Compounds

“…Actually, 50 mg of trans-1 were processed. After 17 cycles, 18 = −4.8 c ≅ 0.5%, CHCl3) were isolated with e.e. higher than 99% (Figure 5), together with 8.5 mg of an intermediate fraction as a mixture of the two enantiomers.…”

“…Several MedChem groups have focused on the synthesis of new molecular entities based on γor δ-lactam scaffolds as highly versatile key intermediates, leading to the discovery of new anti-trypanosomal, anti-biofilm and anti-inflammation agents [14][15][16][17][18]. For instance, Delong et al studied novel α-methylene-γ-lactams, α-arylidene-γ and δ-lactams, with novel antifungal properties against Colletotrichum orbiculare [19], whereas Davoren et al prepared a series of molecules with lactam scaffolds and identified a number of γ-and δ-lactams able to function as positive allosteric modulators (PAMs) of muscarinic receptors (M1) [20].…”

“…Lastly, by applying a combined molecular modelling-STD NMR approach, our group recently identified a promising ligand with a δ-lactam scaffold able to bind the RNA-binding protein HuR [21][22][23], which interacts with target mRNAs, leading to the formation of HuR-mRNA complexes involved in several physio-pathological conditions [24][25][26]. Several MedChem groups have focused on the synthesis of new molecular entities based on γor δ-lactam scaffolds as highly versatile key intermediates, leading to the discovery of new anti-trypanosomal, anti-biofilm and anti-inflammation agents [14][15][16][17][18]. For instance, Delong et al studied novel α-methylene-γ-lactams, α-arylidene-γ and δ-lactams, with novel antifungal properties against Colletotrichum orbiculare [19], whereas Davoren et al prepared a series of molecules with lactam scaffolds and identified a number of γand δ-lactams able to function as positive allosteric modulators (PAMs) of muscarinic receptors (M1) [20].…”

Dose-Dependent Effects of a Novel Selective EP4 Prostaglandin Receptor Agonist on Treatment of Critical Size Femoral Bone Defects in a Rat Model

“…Cayman Chemical (Ann Arbor, MI, USA) developed a series of small molecule difluorolactam EP 4 receptor agonists, including KMN-159, the EP 4 receptor agonist used in this study. It exhibits high selectivity and efficacy at the EP 4 receptor [ 18 ], is chemically stable, rapidly cleared from the organism through urine, and has simpler storage conditions than BMP-2 [ 19 ].…”

Improved homology modeling of the human & rat EP4 prostanoid receptors

“…GlaxoSmithKline, Roche Holding AG, Ono Pharmaceuticals and Merck and Co. have targeted EP 4 with γ-lactam SAR programs [3, 8]. Multiple industrial drug-discovery programs have utilized the rat EP 4 (rEP 4 ) receptor as a surrogate for the human EP 4 (hEP 4 ) receptor in screening assays and animal models to identify lead compounds for development [9–15].…”