O Design Of Eicosanoid Drugs

The ability to capitalize successfully on the highly potent biologic effects of the various eicosanoids to develop new therapeutic agents currently seems an unfulfilled promise to medicinal chemists. Although these natural substances are highly potent effectors of various biologic functions, their use as drugs has been hampered by the following factors: (a) their chemical complexity and relative instability, which have limited, to some extent, their large-scale production and formulation for clinical testing; (b) their susceptibility to rapid degradation in vivo (Fig. 26.3), which limits their effective bioactive half-life; and (c) their propensity to affect diverse tissues (particularly the gastrointestinal tract, which may lead to severe nausea and vomiting) if they enter the systemic circulation, even in small amounts. Caution is always recommended with the use of prostaglandin analogs in women of childbearing age because of their potential for inducing dramatic contraction of uterine muscles, possibly leading to miscarriage.

Several approaches have been used to overcome these difficulties. First, structural analogs of particular eicosanoids have been synthesized that are more resistant to chemical and metabolic degradation but maintain, to a large extent, a desirable biologic activity. Although commercial production and formulation may be facilitated by this approach, biological potency of these analogs is usually reduced by several orders of magnitude. Also, systemic side effects may become troublesome because of broader tissue distribution as a result of the increased biological half-life.

Structural alterations of the eicosanoids have been aimed primarily at reducing or eliminating the very rapid metabolism of these potent substances to relatively inactive metabolites (see Fig. 26.3). Several analogs are presented in Table 26.3 to illustrate approaches that have led to potentially useful eicosanoid drugs. Methylation at the 15- or 16-position will eliminate or reduce oxidation of the essential 15-(S)-alcohol moiety. Esterification of the carboxylic acid function may affect formulation or absorption characteristics of the eicosanoid, whereas esterase enzymes in the bloodstream or tissues would be expected to quickly regenerate the active therapeutic agent. Somewhat surprisingly, considering the restrictive con-figurational requirements at the naturally asymmetric centers, various hydrophobic substituents (including phenyl rings) may replace the saturated alkyl chains, with retention of bioactivity.

A second major approach has been aimed at delivering the desired agent, either a natural eicosanoid or a modified analog, to a localized site of action by a controlled delivery method. The exact method of delivery may vary according to the desired site of action (e.g., uterus, stomach, lung) but has included aerosols and locally applied suppository, gel formulations, or cyclodextrin complexes. The recent commercial development of prostaglandin PGF-type derivatives for use in the eye to lower intraocular pressure (IOP) in glaucoma (discussed under "Prostaglandins for Ophthalmic Use") relies on their potent therapeutic effects coupled with their limited distribution from this site of administration.23

6-Keto-PGF1a Figure 26.3 • Eicosanoid degradation.

TABLE 26.3 Prostaglandin Analogs under Investigation as Receptor Ligands and Future Drug Candidates



EP2-receptor ligand

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