Synthesis and evaluation of γ-lactam analogs of PGE2 as EP4 and EP2/EP4 agonists

Kambe, Tohru; Maruyama, Toru; Nakai, Y.; Oida, Hiroji; Maruyama, Takayuki; Abe, Nobutaka; Nishiura, Akio; Nakai, Hisao; Toda, Masaaki

doi:10.1016/j.bmc.2012.04.008

Cited by 9 publications

(4 citation statements)

References 16 publications

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“…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]. 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].…”

Section: Introductionmentioning

confidence: 99%

“…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%

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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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Section: Introductionmentioning

confidence: 99%

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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show abstract

“…10 Therefore, a number of prostaglandin analogs that are resistant to rapid inactivation have been developed for clinical use. [11][12][13][14][15] Misoprostol is a prostaglandin analogue used for the treatment and prevention of peptic ulcers caused by nonsteroidal anti-inflammatory drugs. 16 More recently, this analogue has been used to induce labor 17 and treat postpartum hemorrhage.…”

Section: Introductionmentioning

confidence: 99%

Cell-based biological evaluations of 5-(3-bromo-4-phenethoxybenzylidene)thiazolidine-2,4-dione as promising wound healing agent

Piao

Song

Cho

2015

Bioorganic & Medicinal Chemistry

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“…However, local administration of PGE 2 is an unacceptable therapeutic option for human diseases because of the biological instability of prostaglandins: PGE 2 has a short lifetime in vivo because it is rapidly oxidized to 15-ketoprostaglandins by the NAD þ -dependent cytosolic enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) [19]. Therefore, a number of prostaglandin analogs that are resistant to rapid inactivation have been developed for clinical use [20][21][22][23][24]. We recently showed that 15-PGDH inhibitors elevate PGE 2 levels in IL-1β-stimulated A549 cells [25].…”

Section: Introductionmentioning

confidence: 99%