Chemistry and synthetic development of misoprostol.
Misoprostol is a synthetic prostaglandin which is related structurally to naturally occurring prostaglandin E1 (PGE1). PGE1 has long been recognized as an effective inhibitor of gastric acid secretion when administered intravenously. However, three major problems have prevented the use of natural PGE1 as a therapeutic treatment for peptic ulcer disease. Each of these problems, lack of oral activity, side-effects, and short duration of action, has been overcome by the chemical development of misoprostol from PGE1. The major structural alteration of PGE1 was the relocation of the 15-hydroxy group to the adjacent 16-position. This important modification significantly reduced typical prostaglandin side-effects such as diarrhea, yet retained full antisecretory potency and also provided a degree of oral activity. The second modification was the addition of a methyl group to carbon-16 to prevent metabolic oxidation of the hydroxy group. This structural change greatly increased both oral potency and duration of action and completed the synthetic development of misoprostol. Misoprostol is chemically unstable at room temperature, as is PGE1. This problem has been solved by pharmaceutical formulation studies which led to a stable and solid dosage form.
D000527:Alprostadil / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D000897:Anti-Ulcer Agents / Q000138:chemical synthesis; D055598:Chemical Phenomena; D002621:Chemistry; D003967:Diarrhea / Q000139:chemically induced; D004355:Drug Stability; D005744:Gastric Acid / Q000378:metabolism; D016595:Misoprostol; D011458:Prostaglandins E / Q000145:classification; D013329:Structure-Activity Relationship
D000897:Anti-Ulcer Agents; D011458:Prostaglandins E; D016595:Misoprostol; D000527:Alprostadil