Prostaglandins

Prostaglandins occur in nearly all mammalian tissues, but only at very low concentrations. PGEt and PGFia were initially isolated from sheep seminal plasma, but these compounds and PGD2, PGE2, and PGF2a are widely distributed. Animal sources cannot supply sufficient amounts for drug usage. The soft coral Plexaura homomalla (sea whip) from the Caribbean has been identified as having very high (2-3%) levels of prostaglandin esters, predominantly the C-15 epimerof PGA2 (1 -2%) with related structures. Prostaglandins of the A-, E-, and F-types are widely distributed in soft corals, especially Plexaura, but these are unlikely to provide a satisfactory and renewable natural source. Considerable effort has been exerted on the total synthesis of prostaglandins and their interconversions, and the high level of success achieved has opened up the availability of compounds for pharmacological testing and subsequent drug use. Synthetic analogues have also been developed to modify or optimize biological activity. The studies have demonstrated that biological activity is effectively confined to the natural enantiomers; the unnatural enantiomer of PGE1 had only 0.1% of the activity of the natural isomer.

The prostaglandins display a wide range of pharmacological activities, including contraction and relaxation of smooth muscle of the uterus, the cardiovascular system, the intestinal tract, and of bronchial tissue. They may also inhibit gastric acid secretion, control blood pressure and suppress blood platelet aggregation. Some of these effects are consistent with the prostaglandins acting as second messengers, modulating transmission of hormone stimulation and thus metabolic response. Some prostaglandins in the A and J series have demonstrated potent antitumour properties. Since the prostaglandins control many important physiological processes in animal tissues, their drug potential is high, but the chances of precipitating unwanted side-effects are also high, and this has so far limited their therapeutic use.

There is, however, much additional scope for controlling the production of natural prostaglandins in body tissues by means of specific inhibitors. Indeed it has been found that some established non-steroidal anti-inflammatory drugs (NSAIDs), e.g. aspirin, indometacin, and ibuprofen, inhibit early steps in the prostaglandin biosynthetic pathway that transform the unsaturated fatty acids into cyclic peroxides. Thus aspirin is known to irreversibly inactivate the cyclooxygenase activity (arachidonic acid ^ PGG2), though not the peroxidase activity (PGG2 ^ PGH2), by selective acetylation of a serine residue of the enzyme; ibuprofen and indometacin compete with arachidonic acid at the active site and are reversible inhibitors of the cyclooxygenase. A recent discovery is that two forms of the cyclooxygenase enzyme exist, designated COX-1 and COX-2. COX-1 is expressed constitutively in most tissues and cells and is thought to control synthesis of those prostaglandins important for normal cellular functions such as gastrointestinal integrity and vascular homeostasis. COX-2 is not normally present, but is inducible in certain cells in response to inflammatory stimuli, resulting in enhanced prostaglandin release in the CNS and inflammatory cells with the characteristic inflammatory response. Current NSAIDs do not discriminate between the two COX enzymes, and so this leads to both therapeutic effects via inhibition of COX-2, and adverse effects such as gastrointestinal problems, ulcers, and bleeding via inhibition of COX-1. Because of differences in the nature of the active sites of the two enzymes, it has now been possible to develop agents that can inhibit COX-2 rather than COX-1 as potential new anti-inflammatory drugs. The first of these, meloxicam and rofecoxib, have recently been introduced for relief of pain and inflammation in osteoarthritis. The anti-inflammatory activity of corticosteroids correlates with their preventing the release of arachidonic acid from storage phospholipids, but expression of COX-2 is also inhibited by glucocorticoids.

The role of essential fatty acids (see page 46) such as linoleic and y-linolenic acids, obtained from plant ingredients in the diet, can now be readily appreciated. Without a source of arachidonic acid, or compounds which can be converted into arachidonic acid, synthesis of prostaglandins would be compromised, and this would seriously affect many normal metabolic processes. A steady supply of prostaglandin precursors is required since prostaglandins are continuously being synthesized and then deactivated. Prostaglandins are rapidly degraded by processes which include oxidation of the 15-hydroxyl to a ketone, reduction of the 13,14-double bond, and oxidative degradation of both side-chains.

A major area of application of prostaglandins as drugs is in obstetrics, where they are used to induce abortions during the early to middle stages of pregnancy, or to induce labour at term. PGE2 (dinoprostone) (Figure 3.19) is used in both capacities, whilst PGF2a (dinoprost) is now less commonly prescribed and restricted to abortions. PGF2a is rapidly metabolized in body tissues (half-life less than 10 minutes), and the modified version 15-methyl PGF2a (carboprost) has been developed to reduce deactivation by blocking oxidation at position 15. Carboprost is produced by oxidizing the 15-hydroxyl in a suitably-protected PGF2a, then alkylating the 15-carbonyl with a Grignard reagent. Carboprost is effective at much reduced dosage compared with dinoprost, and is of value in augmenting labour at term, especially in cases where ergometrine (see page 375) or oxytocin (see page 415) are ineffective. Gemeprost is another unnatural structure and is used to soften and dilate the cervix in early abortions. These agents are usually administered vaginally.

PGE1 (alprostadil) differs from PGE2 by having unsaturation in only one side-chain. Though having effects on uterine muscle, it also has vasodilator properties, and these are exploited for maintaining new-born infants with congenital heart defects, facilitating blood oxygenation prior to corrective surgery. The very rapid metabolism of PGEi means this drug must be

CO2H

CO2H

OH dinoprost (PGF2a)

OH dinoprost (PGF2a)

co2h co2h

Me OH

carboprost (15-methyl PGF2a)

co2h

Me OH

carboprost (15-methyl PGF2a)

co2h

OH dinoprostone (PGE2)

OH dinoprostone (PGE2)

co2h co2h

alprostadil

alprostadil

CO2Me

gemeprost

CO2Me

gemeprost ho'

co2h

Me misoprostol co2h

Me misoprostol

CO2H

co2h

epoprostenol / prostacyclin (PGI2)

OH iloprost

CO2Pri

latanoprost

CO2Pri

epoprostenol / prostacyclin (PGI2)

OH iloprost latanoprost

Figure 3.19

delivered by continuous intravenous infusion. Alprostadil is also of value in male impotence, self-injectable preparations being used to achieve erection of the penis. An interesting modification to the structure of PGE1 is found in the analogue misoprostol. This compound has had the oxygenation removed from position 15, transferred to position 16, plus alkylation at position 16 to reduce metabolism (compare 15-methyl PGF2a above). These modifications result in an orally active drug which inhibits gastric secretion effectively and can be used to promote healing of gastric and duodenal ulcers. In combination with non-specific NSAIDs, it can significantly lower the incidence of gastrointestinal side-effects such as ulceration and bleeding.

PGI2 (epoprostenol, prostacyclin) reduces blood pressure and also inhibits platelet aggregation by reducing calcium concentrations. It is employed to inhibit blood clotting during renal dialysis, but its very low half-life (about 3 minutes) again necessitates continuous intravenous administration. The tetrahydrofuran ring is part of an enol ether and is readily opened by hydration, leading to 6-ketoprostaglandin F1a (Figure 3.20). Iloprost (Figure 3.19) is a stable carbocyclic analogue of potential use in the treatment of thrombotic diseases.

Latanoprost (Figure 3.19) is a recently introduced prostaglandin analogue which increases the outflow of aqueous humour from the eye. It is thus used to reduce intraocular pressure in the treatment of the eye disease glaucoma.

,CO2H

hydrolysis of enol ether rJ_>H

HO OH

PGI2

HO OH

PGI2

Metabolite Pgi2

Figure 3.20

CO2H

CO2H

6-keto PGF1o

6-keto PGF1o

Figure 3.20

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