Thomas K. Schaaf

Structure activity studies leading to a tissue-selective hypotensive prostaglandin analog, 13,14-dihydro-16-phenyl-ω-tetranor PGE2

Abstract During our systematic search for prostaglandins with improved tissue selectivity and metabolic stability, we synthesized a series of PGE 2 analogs in which the n-amyl carbinol side chain was systematically substituted by a phenyl ring, based on structural considerations incorporating the 17,18- cis -double bond of PGE 3 into an aromatic ring. These compounds were evaluated for uterine stimulant, bronchodilator and hypotensive activity. Among the divergent biological profiles exhibited by these analogs, noteworthy was the tissue-selective hypotensive profile displayed by 13,14-dihydro-16-phenyl-ω-tetranor PGE 2 .

Chapter 9: Prostaglandin Structure-Activity Relationships

Publisher Summary Extensive pharmacological evaluation of unique natural products like extremely potent C 20 fatty acids has, however, uncovered a broad spectrum of activities, both in animals and man. Despite the demonstration of potent pharmacological activity, the original optimistic predictions of clinical utility for the natural prostaglandins have not been realized. The lack of selectivity and oral efficacy, chemical instability, and short duration of action of the natural materials have limited their commercial use to prostaglandin F 2α , (dinoprost tromethamine) as an abortifacient and prostaglandin E 2 (dinoprostone) both as an abortifacient and inducer of labor. Conclusions concerning prostaglandin analog activity must be accepted with caution unless data for several biological assays is presented because inactivity in one assay may be merely a reflection of selectivity. This chapter summarizes a number of useful prostaglandin structure–activity relationships (SAR), derived over the past decade. As the activity of the natural prostaglandins differs widely with changes in number, type, and stereochemistry of oxygenated substituents, it seems reasonable that cyclopentane ring analogs would exhibit different pharmacological profiles. The interesting concept of substituting a heteroatom for a ring carbon (and its pendant oxygen function) has been investigated with the synthesis of 8-aza, 9-thia, 10-oxa, 11-oxa, 11-thia, and 9, 11-dioxa analogs. Animal studies with many of the modified prostaglandins suggest that some may be superior to the natural materials. However, with the exception of the 15- and ldmethylated prostaglandins little has been reported concerning the therapeutic effects of prostaglandin analogs in man.

Synthesis of tritium-labeled N-acetyl PGE2 carboxamide (CP-27,987)

The preparation of N-acetyl PGE2 carboxamide (CP-27,987) regioselectively labeled at C-18 and C-19 with tritium is described. The overall radiochemical yield was 8.0% at a specific activity of 0.49 Ci/mmole. The synthesis employed is applicable to the preparation of tritium labeled natural prostaglandins and a variety of analogs.

Chapter 19. Modulation of the Arachidonic Acid Cascade

Publisher Summary Prostaglandins are biosynthesized from arachidonic acid. Arachidonic acid serves as a precursor for a virtual cascade of acidic lipids, each possessing distinct and profound pharmacological activities. Prostacycline (PGX) is both a potent inhibitor of platelet aggregation and an arterial vasodilator. The endoperoxides decompose into the fatty acid HHT. This transformation is probably a non-enzymatic artifact and no biological activity. Another fatty acid, HETE, formed from arachidonic acid by a platelet lipoxygenase has been found to exhibit chemotactic activity for neutrophils and eosinophils. Agonists design to exploit the potential therapeutic uses of the prostaglandins. Prostaglandin activities are to modulate the enzymes that control the tissue levels. Anti-inflammatory steroids exhibit potent inhibitory effects on prostaglandin production in rheumatoid synovial. Bradykinin releases prostaglandins from phospholipid in a variety of systems, an effect thought to augment the activities of this peptide. The local anaesthetic tetracaine and psychotropic drug meprobamates are reported to inhibit prostaglandin biosynthesis at the phospholipase level. Non-steroidal anti-inflammatory (NSAI) agents owe their pharmacological activity to the inhibition of prostaglandin biosynthesis (PGBS). Both aspirin and dexamethasone depress the acute inflammatory response to carrageenin in rats. Deplete of arachidonic acid suggests that the activities other than PGBS inhibition contribute to the anti-inflammatory effects of both steroids and NSAl agents. Inhibition of PGBS by a series of NSAl agents appear to be better correlated with the analgesic effects than with the anti-inflammatory activity.

Radioimmunoassay for sulprostone

The development of a radioimmunoassay for measuring subnanogram amounts of the prostaglandin uterine stimulant, sulprostone (N-methanesulfonyl 16-phenoxy-omega-tetranor PGE2 carboxamide), is described. The 9-carboxymethoxime derivative of sulprostone was coupled to keyhole limpet hemocyanin to prepare the immunogen, and to tyramine to yield a precursor suitable for radioiodination. The antiserum generated from rabbits was specific for sulprostone, showing cross reactivities of less than 0.1% against PGE2, PGF2 alpha, and known sulprostone metabolites. The range for routine assay of sulprostone was 10-300 pg which corresponded to 50-1500 pg/ml of plasma. The coefficient of variation for replicate analyses on the same sample was 8-12%. The assay was used to measure the plasma levels of sulprostone in patients who had received the drug intramuscularly.