Raphael Pappo

SC-29333: A potent inhibitor of canine gastric secretion

The gastric antisecretory effects of SC-29333, a novel prostaglandin E1 analog, were compared to the reference standard PGE1 methyl ester (PGE1ME) in gastric 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 pepsin 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 μg/kg, respectively. Unlike PGE1ME, SC-29333 was orally effective at doses of 10–30 μg/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.

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 degrees 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.

NEW SYNTHETIC APPROACH IN THE PROSTAGLANDIN FIELD

The aim of t h i s work was t o d e v i s e a p r a c t i c a l syn the s is of new p r o s t a g l a n d i n ana logs and t o e v a l u a t e t h e m w i t h r e g a r d t o t h e i r b i o l o g i c a l a c t i v i t y . A s econdary pu rpose w a s t h e t o t a l s y n t h e s i s of known p r o s t a g l a n d i n s . P o r t i o n s of oux work have been d e s c r i b e d p r e v i o u s l y ( C o l 1 i n s e t a l l 1968) .

Influence of the position of the side chain hydroxy group on the gastric antisecretory and antiulcer actions of E1 prostaglandin analogs

The influence of transposing the C-15 hydroxy group of prostaglandin E1 methyl ester (PGE2ME) on gastric antisecretory and antiulcer actions was investigated. The compound (+/-)15-deoxy- 16alpha, beta-hydroxy PGE1ME (SC-28904) was equipotent to the reference standard PGE1ME in suppressing histamine-stimulated gastric secretion in the Heidenhain pouch (HP) dog. In contrast to PGE1ME, SC-28904 was longer acting when administered intravenously and also showed significant oral activity in the histamine-stimulated gastric fistula dog. SC-28904 was also equipotent to PGE1ME (range of active doses of 0.5 to 5.0 mg/kg, s.c.) in inhibiting forced-exertion gastric ulceration in rats. The compound (+/-)15-deocy-17alpha, beta-hydroxy PGE1ME (SC-30963) was an inactive antisecretory agent in the dog at the 1.0 mg/kg i.v. bolus dose. This dose was 100 times greater than the active antisecretory dose of PGE1ME. Likewise, SC-30693, when administered subcutaneously at a 5.0 mg/kg dose, was also totally inactive in preventing gastric ulcers induced by forced exertion in rats. The important implications of this work are that some of the receptor sites for the PGE1 molecule could easily accomodate the side chain hydroxy group either in the C-15 or C-16 position. Moreover, the hydroxy group in the latter position significantly improved the biological activity of PGE1ME.

Renal Electrolyte Effects of Synthetic 18-Hydroxylated Steroids in Adrenalectomized Rats

Summary Several synthetic 18-hydroxy-lated steroids lacking oxygen at carbon 11 were tested for mineralocorticoid properties in acute studies using adrenalectomized rats. A multiple dose assay with DCA described relative potencies of 4, 8 and 5% parenterally for 18-OH-DCA by the criteria of Na retention, K loss and reduction of the Na/K ratio in the urine. Approximately the same order of potency was found for the alcohol derivative, 18-OH-DOC. 18-OH-Progesterone was ineffective as a mineralocorticoid. No significant anti-mineralocorticoid activity was found with 18-OH-progesterone or 18-OH-DCA.

Chapter 29. Steroids

Publisher Summary This chapter elaborates the development and preparation of steroids. Preliminary reports on a new fragmentation of α,β-epoxy ketones to acetylenes and carbonyl-containing products showed that the reaction can be of general application. Tosylhydrazones on reaction with alkylithium reagents give olefins in high yield. This new synthesis allowed for example the preparation of 16-androstene from androstan-17-one in quantitative yield. Reduction of carbonyl functions to methylene can be effected electrochemically or by treatment of the steroid ketones with powdered zinc in acetic anhydride saturated with hydrogen chloride at room temperature. A convenient method for transposing the oxygen of a carbonyl to an adjacent methylene involved condensing the ketone with an aromatic aldehyde, reduction of the resulting arylidene ketone with lithium aluminum hydride-aluminum chloride reagent to the corresponding desoxy compound, followed by ozonolysis to the new ketone. The Westphalen rearrangement of some 3β-substituted-6β-acetoxy-5α-hydroxycholestanes has also been studied and the products and kinetics are shown to be dependent on the nature of the 3-substitutents.

Chapter 30. Steroids

Publisher Summary A major breakthrough in the field of steroids is the elucidation of the biosynthesis of sterols. Strong evidence has been obtained showing that squalene 2,3-oxide is an intermediate in the conversion of squalene to cholesterol. Other important contributions are in the area of total synthesis of steroids. The selective reduction of steroids by homogeneous catalytic hydrogenation has been studied and shown to be promising. A new angular methylation procedure, at C1, involving the Simmons–Smith reagent is discovered, thus extending the usefulness of the Smith–Torgov total synthesis of 19-norsteroids. A total synthesis of resolved 17β-hydroxy-des-A-androst-9-en-5-one has been described in connection with the preparation of 10α-methyl steroids. Conessine is degraded by an elegant and simple method to 13β-cyano-18-nor-5α-androstane derivatives .The photolysis of 3-oxo-4,5-epoxides led to 3,5-dioxo-10 (5→4 )abeo steroids. Work is continuing on the isolation and identification of new steroidal alkaloids from boxwood species, such as Buxus balearica, Buxus malayana, Buxus rolfei, Buxus sempervirens, and Buxus koreana. With few exceptions, these alkaloids have an unusual skeleton containing a cyclopropane ring and are derived from the 4,4′,14α trimethyl-9β, 19-cyclo-5α-pregnane system.