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Prostaglandins (PGs) in the E-series exhibit potent gastric antisecretory activity, but can also cause diarrhea, which is mediated via PGE receptors. SC-46275, an omega-chain cyclopentenyl analog of the E-type PG enisoprost, was evaluated with other E-PGs for PGE receptor binding activity in gastric and intestinal tissues. SC-46275, enisoprost, misoprostol and PGE1 were first evaluated in enriched canine gastric parietal cells with [3H]misoprostol free acid binding and subsequently with [3H]PGE1 binding in canine intestinal tissues where misoprostol free acid had weak receptor binding activity. The receptor binding potency of SC-46275 (IC50, 0.013 mM) in enriched canine parietal cell preparations was found to be much greater than misoprostol and enisoprost (IC50, 10 and 8 nM), whereas PGE1 had the least potency (IC50, 37 nM). Similar relative potencies for these PGs were also obtained in the inhibition of histamine-stimulated acid secretion in enriched parietal cell preparations. In small intestinal mucosal and muscle membranes, the receptor binding potency of SC-46275 (IC50, 13 and 20 microM) was much less than misoprostol or enisoprost (IC50, 0.39-1.2 microM) and substantially less than PGE1 (IC50, 0.017 and 0.066 microM). This weak binding activity of SC-46275 in intestinal tissues is consistent with its reported weak diarrheagenic activity in the rat. These results suggest that SC-46275 binds preferentially to gastric vs. intestinal PGE receptors and is specific for the EP3 receptors.

SC-30249 is the active isomer of misoprostol responsible for its mucosal protective effects against nonsteroidal anti-inflammatory drugs (NSAIDS). Linkage of SC-30249 to a polybutadiene polymer results in a delivery system (SC-55307) that releases the active component only under the acidic conditions of the stomach. This approach could be used to minimize side effects and systemic availability of synthetic prostaglandins. These studies were done to determine whether uterotonic activity could be recorded after treatment with SC-55307. Female beagles were implanted with uterine strain gauge force transducers, allowed 10 days for recovery and treated with estrogen to sensitize the uterus to the actions of prostaglandins. Base-line responses were determined with SC-30249, i.v., and then a randomized series of four treatments were given: SC-30249, IG, 10 micrograms/kg; SC-55307, IG, equivalent to 30 and 100 micrograms/kg of SC-30249; and a blank polymer control. HCI was given IG to provide an acid environment in the stomach, uterine responses were obtained for up to 4 h and plasma concentrations of SC-30249 free acid was determined. No uterotonic effect was seen after a low dose of SC-55307, whereas the high dose caused a brief but statistically significant increase equal to 8.8% and 17.8% of the responses to SC-30249, i.v. and IG, respectively. Peak plasma levels of SC-30249 free acid were 176.4 +/- 17.4 and 59.5 +/- 10.6 pg/ml after SC-30249, i.v. and IG, respectively, but were only 3.9 +/- 1.7 and 15.5 +/- 6.6 pg/ml after low and high doses of SC-55307, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

SC-53450 is a new polybutadiene-based polymer system with an acid labile diisopropyl silyl ether linker to which the active isomer of misoprostol (SC-30249) is attached covalently at position C-11. It was studied in rats and dogs to define its profile of gastrointestinal effects relative to misoprostol-hydroxypropyl methylcellulose (HPMC) and the systemic availability of prostaglandin from the polymer. Results of rat studies indicate that SC-53450 has a spectrum of mucosal protective activity similar to misoprostol-HPMC, being protective against indomethacin-induced gastric, cysteamine/indomethacin-induced duodenal and indomethacin-induced lower small bowel damage. SC-53450, in contrast to misoprostol-HPMC, was not diarrheagenic in the rat when administered intragastrically. The observation that SC-53450 is more than 4 times more potent than misoprostol-HPMC suggests the possibility of sustained gastric availability of the prostaglandin SC-30249. SC-53450 exhibited gastric antisecretory activity in histamine-stimulated gastric fistula dogs and protected against acidified aspirin-induced gastric damage in normal fasted beagles. Rat and dog experiments indicate that little, if any, polymer-derived prostaglandin is available systemically, suggesting SC-53450 will have reduced abuse potential in abortion induction. SC-53450 is a potential candidate to replace the present misoprostol formulation in the marketplace for the prevention of nonsteroidal anti-inflammatory drug-induced gastric damage.

The synthetic prostaglandin, SC-46275, an omega chain cyclopentenyl analog of enisoprost, was studied to determine its gastric antisecretory potency and duration of action in meal-stimulated innervated (Pavlov) pouch dogs and its p.o. bioavailability in unoperated fasted dogs. SC-46275 exhibited potent antisecretory activity when administered directly into the gastric pouch, the ED50 being 0.01 micrograms/kg. It had a long duration of antisecretory action; significant (P less than or equal to .05) inhibition of total acid output was observed 16 hr after intrapouch administration of 0.03 micrograms/kg. At this dose p.o., neither SC-46275 nor its free acid metabolite was detected in plasma. These data indicate that SC-46275 has novel properties: it is a potent, long-acting gastric antisecretory agent which is not readily available systemically after p.o. administration. Thus, potential systemic side effects are expected to be absent or minimized at doses of SC-46275 which inhibit gastric acid secretion, and therefore it might be useful in peptic ulcer disease.