The gastric antisecretory effects of SC-29333, a novel prostglandin E1 analogs, were compared to the reference standard PGE1 methyl ester (PGE1ME) in gsstric fistula and Heidenhain pouch dogs. Secretion was stimulated submaximally by continuous intravenous infusion of either histamine or pentagastrin. Meal-stimulated gastric secretory studies were also conducted. SC-29333 effectively inhibited volume, acid output, and papsin secretion, in a dose-dependent manner. Intravenously (i.v.), SC-29333 was found to be approximately 30 times more potent than PGE1ME. The ranges of active i.v. bolus doses for SC-29333 and PGE1ME were 0.3-3.0 and 10-30 mug/kg, respectively. Unlike PGE1ME, SC-29333 was orally effective at doses of 10-30 mug/kg and was considerably better tolerated and longer acting than PGE1ME at active antisecretory doses. It is concluded, therefore, that SC-29333 is a potent, long-acting, orally effective inhibitor of gastric secretion in the dog.
The preparation and gastric antisecretory activity of a series of 15-deoxy-16-hydroxyprostaglandin analogues are described. The compounds were tested intravenously in histamine-stimulated Heidenhain pouch dogs in relation to the reference standards PGE1 and PGE1 methyl ester (PGE1ME). The parent compound of this seris, (+/-)-15-deoxy-16alpha,beta-hydroxyprostaglandin E1 methyl ester (3), was found to be equipotent to the reference standard PGE1ME. Methylation at C-16 of 3 produced 8 which was found to be some 40 times more potent than PGE1. In sharp contrast, addition of two methyl groups to 3 at C15 or C17 markedly reduced the antisecretory action. The 16-ethyl analogue of 3 also showed reduced potency. Removal or epimerization of the C-11 hydroxy group of 8 reduced the activity. Likewise, hydrogenation or changing the stereochemistry of the 13,14 double bond from trans to cis decreased the activity. On the other hand, omega-homologation of 8 or the introduction of a cis-5,6 double bond did not affect the potency. From these studies, it appears that 8, 16, and 17 possess optimum gastric antisecretory effects in this series.
We previously reported the prostaglandin analogue SC-29333 [( ~)(16RS)-15deoxy-l6 hydroxy,-16-methyl prostaglandin El methyl ester] to be a potent inhibitor of gastric secretion in animals. SC-29333 is comprised of four stereoisomers in approximately equal proportions. It is believed the major antisecretory activity of SC-29333 results from one isomer, SC-30249 (16S-16-hydroxy-16-methyl, 15deoxy-PGE, methyl ester). Our purpose was to investigate the canine gastric antisecretory action of SC-30249 relative to SC-29333. The studies were carried out in maximally stimulated (histamine) Heidenhain pouch (HP) and gastric fistula (GF) dogs. Administered intravenously (i.v.) to HP dogs at the steady-state plateau of gastric secretion, SC-30249 was found to be approximately three times more potent than SC-29333. Administered intragastrically to GF dogs, SC-30249 is approximately ten times more potent as an inhibitor of gastric secretion than SC-29333. SC-30249 (1 .O pglkg, i.v.) completely inhibited meal-stimulated gastric secretion but had no significant effect on postprandial serum gastrin concentration. SC-30249 shared with SC-29333 the capability of totally antagonizing the histamine-stimulated gastric secretion in HP dogs without reducing gastric mucosal blood flow. These studies indicate that SC-30249 is a potent gastric antisecretory agent that merits clinical evaluation.
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