A novel series of prostaglandin analogues with a seven-membered ring scaffold was designed, synthesized, and evaluated for the functional activation of prostaglandin receptors to identify potent and subtype-selective FP and EP3 dual agonists. Starting from the prostacyclin derivative 5b, a nonselective agonist for prostaglandin receptors, replacement of the core structure with an octahydro-2H-cyclopenta [b]oxepine scaffold led to the discovery of the potent and selective FP and EP3 dual agonist 11b as a lead compound for the development of an antiglaucoma agent. KEYWORDS:Prostaglandin, dual agonist, FP receptor, EP3 receptor, GPCR, glaucoma P rostaglandins are the products of cyclooxygenase-catalyzed metabolism of arachidonic acid that exert a wide variety of biological actions through G-protein coupled prostaglandin receptors. Prostaglandin E 2 (PGE 2 ), PGF 2α , PGD 2 , PGI 2 , and thromboxane A 2 (TXA 2 ) preferentially activate the EP, FP, DP, IP, and TP receptor, respectively. There are four distinct subtypes of EP receptor, EP1, EP2, EP3 and EP4, as well as two subtypes of DP receptor, DP1 and DP2.Glaucoma is a chronic ocular disease characterized by progressive optic neuropathy and visual field loss. There are many types of treatment for glaucoma based on various mechanisms. The primary treatment is to control intraocular pressure (IOP) by topical administration of an IOP lowering agent. Prostaglandin analogues (PGAs) such as latanoprost, 1 travoprost, 2 and tafluprost 3,4 (Figure 1) reduce IOP by targeting the prostaglandin FP receptor. Currently, such FP agonists are the most effective IOP-lowering agents. However, recently, a novel mechanism of action for PGAs via the prostaglandin EP3 receptor has been reported. 5,6 Topically applied EP3 receptor agonists have demonstrated the potential to reduce IOP in animals. 7 These findings inspired us to identify a small molecule that selectively activates both the FP and EP3 receptors, which could potentially have a superior IOP-lowering effect compared with PGAs. 8 Herein, we report discovery of the first highly selective FP and EP3 dual agonists with a novel seven-membered prostacyclin scaffold, (5aR,8aS)-octahydro-2H-cyclopenta [b]oxepine.To the best of our knowledge, no potent and selective FP and EP3 dual agonists have been reported. We conducted compound screening of our in-house compound libraries to identify compounds possessing FP and EP3 dual agonist activity. Through this screening, compounds 4, 5a, and 5b were found to show the desired activities. The activity profiles are summarized in Table 1, including data for latanoprost acid (1), travoprost acid (2), and sulprostone (3, Figure 2
Protein S-acylation is a reversible post-translational modification that modulates the localisation and function of many cellular proteins. S-acylation is mediated by a family of zinc finger DHHC domain-containing proteins encoded by 23 distinct ZDHHC genes in the human genome. These enzymes catalyse S-acylation in a two-step process involving auto-acylation of the cysteine residue in the catalytic DHHC motif followed by transfer of the acyl chain to a substrate cysteine. S-acylation is essential for many fundamental physiological processes, and there is growing interest in zDHHC enzymes as novel drug targets for a range of disorders. However, there is currently a lack of chemical modulators of S-acylation either for use as tool compounds or for potential development for therapeutic purposes. In this study, we developed and implemented a novel FRET-based high throughput assay for the discovery of compounds that interfere with auto-acylation of zDHHC2, an enzyme that is implicated in neuronal S-acylation pathways. A screen of >350,000 compounds identified two related tetrazole containing compounds (TTZ-1 and -2) that inhibited both zDHHC2 auto-acylation and substrate S-acylation in cell-free systems. Furthermore, these compounds were also active in HEK293T cells, where they inhibited substrate S-acylation mediated by different zDHHC enzymes, with some apparent isoform selectivity. Resynthesis of the hit compounds confirmed their activity, providing sufficient quantities of material for further investigations. The assays developed herein provide novel strategies to screen for zDHHC inhibitors, and the identified compounds add to the chemical toolbox for interrogating the cellular activities of S-acylation and zDHHC enzymes.
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