Lactams as EP4 prostanoid receptor subtype selective agonists. Part 1: 2-Pyrrolidinones-stereochemical and lower side-chain optimization

Elworthy, Todd R.; Kertesz, Denis J.; Kim, Woongki; Roepel, Michael G.; Quattrocchio-Setti, Lina; Smith, David B.; Tracy, Jahari Laurant; Chow, Audrey; Li, Fujun; Brill, Emma R.; Lach, Leang K.; McGee, Daren; Yang, Diana S.; Chiou, San-San

doi:10.1016/j.bmcl.2004.01.063

Cited by 21 publications

(3 citation statements)

References 14 publications

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“…Interestingly, a notable improvement in EP 4 selectivity over EP 2 was shown by the acetylene-bearing pair 7 / 8 relative to the 3/6 pair. This result is consistent with published SAR programs that show that lactam ω-chain rigidity leads to high EP 4 selectivity over EP 2 …”

Section: Resultssupporting

confidence: 92%

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

et al. 2019

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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.

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Section: Resultssupporting

confidence: 92%

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

et al. 2019

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“…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]. Potent, selective γ-lactam small molecule PGE 2 mimic EP 4 agonists were discovered using these screens and have advanced to various stages of preclinical and clinical development for several indications [9, 16]. Elimination of the stereocenter at the α-chain has been shown to be tolerated, beginning first with the discovery of 8-aza-11-deoxy-PGE 1 [17].…”

Section: Introductionmentioning

confidence: 99%

“…Elimination of the stereocenter at the α-chain has been shown to be tolerated, beginning first with the discovery of 8-aza-11-deoxy-PGE 1 [17]. Highly selective, potent agonists such as Roche 31 (CAY10684) have been reported [16]. Likewise, the role of agonists such as Rivenprost (Ono-4819) within bone health has been well established [14].…”

Section: Introductionmentioning

confidence: 99%

Improved homology modeling of the human & rat EP4 prostanoid receptors

Holt

Morano

et al. 2019

BMC Mol and Cell Biol

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Background The EP 4 prostanoid receptor is one of four GPCRs that mediate the diverse actions of prostaglandin E 2 (PGE 2 ). Novel selective EP 4 receptor agonists would assist to further elucidate receptor sub-type function and promote development of therapeutics for bone healing, heart failure, and other receptor associated conditions. The rat EP 4 (rEP 4 ) receptor has been used as a surrogate for the human EP 4 (hEP 4 ) receptor in multiple SAR studies. To better understand the validity of this traditional approach, homology models were generated by threading for both receptors using the RaptorX server. These models were fit to an implicit membrane using the PPM server and OPM database with refinement of intra and extracellular loops by Prime (Schrödinger). To understand the interaction between the receptors and known agonists, induced-fit docking experiments were performed using Glide and Prime (Schrödinger), with both endogenous agonists and receptor sub-type selective, small-molecule agonists. The docking scores and observed interactions were compared with radioligand displacement experiments and receptor (rat & human) activation assays monitoring cAMP. Results Rank-ordering of in silico compound docking scores aligned well with in vitro activity assay EC 50 and radioligand binding K i . We observed variations between rat and human EP 4 binding pockets that have implications in future small-molecule receptor-modulator design and SAR, specifically a S103G mutation within the rEP4 receptor. Additionally, these models helped identify key interactions between the EP 4 receptor and ligands including PGE 2 and several known sub-type selective agonists while serving as a marked improvement over the previously reported models. Conclusions This work has generated a set of novel homology models of the rEP 4 and hEP 4 receptors. The homology models provide an improvement upon the previously reported model, largely due to improved solvation. The hEP 4 docking scores correlates best with the cAMP activation data, where both data sets rank order Rivenprost>CAY10684 > PGE 1 ≈ PGE 2 > 11-deoxy-PGE 1 ≈ 11-dexoy-PGE 2 > 8-aza-11-deoxy-PGE 1 . This rank-ordering matches closely with the rEP 4 receptor as well. Species-specific differences were noted for the weak agonists Sulprostone and Misoprostol, which appear to dock more readily within human receptor versus rat r...

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Agents Acting on Prostanoid and Thromboxane Receptors

Hall

Peace

Swarbrick

2010

Burger's Medicinal Chemistry and Drug Discovery

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Lactams as EP4 prostanoid receptor subtype selective agonists. Part 1: 2-Pyrrolidinones-stereochemical and lower side-chain optimization

Cited by 21 publications

References 14 publications

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

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

Improved homology modeling of the human & rat EP4 prostanoid receptors

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Lactams as EP4 prostanoid receptor subtype selective agonists. Part 1: 2-Pyrrolidinones-stereochemical and lower side-chain optimization

Cited by 21 publications

References 14 publications

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

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

Improved homology modeling of the human & rat EP4 prostanoid receptors

Agents Acting on Prostanoid and Thromboxane Receptors

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Product

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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

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