Lactams as EP<sub>4</sub>Prostanoid Receptor Agonists. 3. Discovery of<i>N</i>-Ethylbenzoic Acid 2-Pyrrolidinones as Subtype Selective Agents

Elworthy, Todd R.; Brill, Emma R.; Chiou, San-San; Chu, Frances; Harris, Jason; Hendricks, R.; Huang, Jane; Kim, Woongki; Lach, Leang K.; Mirzadegan, Taraneh; Yee, Calvin; Walker, K.

doi:10.1021/jm049290a

Cited by 30 publications

(6 citation statements)

References 19 publications

(20 reference statements)

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“…A first very fruitful modification was the use of five-membered lactams as the core of the PG analogues. The known, racemic, 8-aza-11-deoxyPGE 1 was first found as an agonist of the EP 4 receptor, and further studies have shown that the (12 R ,15 S ) isomer was the most potent derivative 84a…”

Section: 44 Heterocyclic Analoguesmentioning

confidence: 99%

Recent Developments in the Synthesis of Prostaglandins and Analogues

et al. 2007

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Section: 44 Heterocyclic Analoguesmentioning

confidence: 99%

Recent Developments in the Synthesis of Prostaglandins and Analogues

et al. 2007

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“…Generally, methyl 4-mercaptobutanoate 36 was prepared from γ-thiobutyrolactone using relatively expensive bases ( t -BuOK, NaOMe). , We initially screened the conditions of the preparation of 36 followed by substitution reaction of 35 with several bases. The results are summarized in Table .…”

Section: Resultsmentioning

confidence: 99%

An Improved Synthesis of the Selective EP4 Receptor Agonist ONO-4819

et al. 2009

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An improved synthesis of the highly selective EP4-receptor agonist ONO-4819 has been developed. The previous synthesis suffered from several drawbacks, in which a critical one is the difficulty in the removal of byproducts leading to unsatisfactory quality of the active pharmaceutical ingredient (API). Furthermore, on stereoselective reduction of an enone intermediate by binaphthol-modified lithium aluminum hydride, low concentration of the reaction conditions and tedious purification procedures to remove excess binaphthol were critical issues for the manufacturing process of the API. In the improved process, we have developed improved conditions using gamma-thiobutyrolactone as sulfur source instead of potassium thioacetate to introduce the sulfur-containing C4 side chain without formation of byproducts. For stereoselective synthesis of the chiral alcohol, (-)-DIP-chloride reduction is found to be the best method, which can improve not only the enantioselectivity but also the workload for removing the chiral modifier in a purification process. Furthermore, benzoyl and tert-butyldimethylsilyl groups as protecting groups for hydroxyl functions were used for precise process controls of all intermediates. By changing these protecting groups, the purity of ONO-4819 was strictly controlled through crystalline intermediates. Thus, an improved robust process for ONO-4819 with a high chemical purity was developed.

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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%