Synthesis and gastric antisecretory properties of allenic 16-phenoxy-omega-tetranor prostaglandin E analogs.

In order to improve the modest oral activity of PGE2 as an inhibitor of gastric acid secretion, analogs were prepared and tested orally in histamine-challenged rats. Insertion of a double bond at C-4, resulting in the 4,5-allene analog of PGE1, gave a small increase in activity. Introduction of the omega-tetranor-16-phenoxy lower sidechain, a modification known to enhance activity in the PGF series, gave an eight-fold increase in activity. The analog having both modifications (enprostil, 2) showed a six hundred-fold increase in oral antisecretory activity over PGE2, which may reflect a potentiation effect. Modification of enprostil at C-1 (various esters) and at C-11 (11-methyl, 11-deoxy) generally resulted in compounds of high activity while modifications at other sites generally resulted in significant reductions in activity.

Gastric antisecretory and antiulcer properties of enprostil, (+/-)-11 alpha, 15 alpha-dihydroxy-16-phenoxy-17,18,19,20-tetranor-9-oxoprosta- 4,5,13(t)-trienoic acid methyl ester.

Prostaglandins of the E series have been shown, both in animals and humans to produce gastrointestinal antisecretory and antiulcer effects. Enprostil, a modified allenic prostaglandin E was found to be a highly potent inhibitor of gastric HCl secretion in a variety of species. In rats, in which both the pylorus and esophagus were ligated, p.o. ED50 values and 95% CL for inhibiting acid secretion evoked by histamine, pentagastrin and carbachol were 9.9 (6.7-15), 40 (11-145) and 0.83 (0.78-0.89) micrograms/kg, respectively. In inhibiting histamine-evoked acid secretion, enprostil was more potent when administered p.o. than when injected into the duodenum or s.c. When enprostil was injected directly into the pouch of Heidenhein dogs, intense antisecretory activity occurred, ED50 = 0.9 (0.7-1.1) micrograms/kg, whereas, when given p.o. to the main stomach the ED50 was 6.6 (3.2-13.6) micrograms/kg. Administration of cimetidine either p.o. or to the pouch resulted in virtually identical ED50 values, viz., 2.9 and 3.1 mg/kg. Enprostil also inhibited dimaprit- and pentagastrin-induced acid secretion in cats with permanent gastric fistulae. The oral ED50 values for inhibiting acid secretion evoked by these two secretagogues were 2.5 (1.4-4.3) and 0.8 (0.5-1.5) micrograms/kg, respectively. Enprostil was extremely potent in preventing indomethacin plus "cold stress" ulcers in rats. When given orally the ED50 was 0.61 (0.31-1.22) and s.c. it was 22 (9.0-52) micrograms/kg. It was also highly potent in preventing cysteamine-induced duodenal ulcers when given p.o., ED50 = 20 (17-23) micrograms/kg. Thus, enprostil is a highly potent antisecretory and antiulcer agent. It appears to act topically; directly at gastric mucosal sites.

Stimulatory effect of enprostil, an anti-ulcer prostaglandin, on gastric mucus secretion.

Enprostil, a synthetic analogue of prostaglandin E2, is known to be a potent inhibitor of gastric acid secretion, and has marked anti-ulcer activity in rodents. Enprostil was administered in doses ranging from 15 to 250 micrograms/kg to rats prepared using the Shay procedure. Three hours later, the rats' stomachs were removed and processed either for the chemical determination of mucus, or for scanning electron microscopy. For the chemical determination, the secreted gastric juice was removed and the adherent gastric mucus was eluted with 2 M sodium chloride. The anthrone method was used to determine the mucus present. Enprostil was found to significantly increase gastric mucus at a dose of 60 micrograms/kg when measured by the anthrone test. Enprostil administered by the oral route was most effective in stimulating mucus secretion, suggesting a local or topical action of enprostil on mucus-secreting cells. Scanning electron microscopy of rat fundic mucosa after enprostil administration (50 to 100 micrograms/kg) revealed the presence of thin veil-like layers covering the epithelial surface, which was interpreted as an increase in mucus secretion. Higher magnifications (X 2,000) clearly showed the layers of mucus covering the surface epithelial cells. Enprostil's apparent increase of gastric mucus secretion may contribute to its anti-ulcer activity and may promote gastric healing.

Gastric mucosal binding studies with enprostil: a potent anti-ulcer prostaglandin.

The potent antiulcer prostaglandin enprostil binds with high affinity to porcine gastric mucosal tissues. This binding is saturable, dissociable and displaceable by compounds with similar structures. Various characteristics of binding such as pH optimum and displacement potencies suggest that enprostil binds to mucosal PGE2 sites. Structure-activity and gastric mucosal binding relationships were also examined.

11-Deoxy-11 alpha,12 alpha-methanoprostaglandin E2, a potent, short-acting bronchodilator.

11-Deoxy-11 alpha,12 alpha-methanoprostaglandin E2 (1b) and the corresponding methyl ester 7a were highly potent, but short acting, bronchodilators both by the intravenous (80 and 10 times PGE2, respectively) and aerosol (2 and approximately 1 times PGE2) routes, as measured by the Konzett-Rössler assay. The 11 beta,12 beta-methano compound 15a was two orders of magnitude less active than 7a. In rhesus monkeys anesthetized by aerosol administration, 1b was 10-50% as potent as, and had a duration of action similar to, PGE1 in the inhibition of methacholine-induced increases in airway resistance. At doses effective in preventing the methacholine response, 1b increased the heart rate (less than or equal to 30%) and precipitated mild upper airway irritation.

Ascaris-induced respiratory responses in the conscious rhesus monkey.

Reproducible immediate-type respiratory responses were evoked in conscious monkeys, sensitive to inhaled Ascaris suum, for periods up to 18 months. These responses were characterized by decreases in tidal volume and increases in breathing rate that persisted for about 40 min. Maximum changes were seen 3--5 min after exposure to the aerosolized antigen and were often accompanied by coughing and increased movement of the animals within the plethysmograph used for monitoring their ventilatory changes. Significant inhibition of the Ascaris-induced respiratory changes were seen in animals treated with either isoproterenol or cromolyn sodium. However, the latter agent was not effective in reversing histamine-induced ventilatory changes. The conscious monkey appears to be a suitable animal for evaluating potential antiallergic drugs.