Currently, about 80% of the new drug molecules approved for clinical use are chiral, and of these, the vast majority are developed and marketed as single enantiomers. This was not always the case however, and prior to the 1990s most chiral drug substances were manufactured and used as racemic mixtures (equal mixtures of R and S enantiomers). This might seem surprising since we have already noted that the chiral macromolecules of living organisms can usually distinguish between the enantiomeric forms of drug species. It turns out however that the separation of drug enantiomers is not a trivial task, especially when it comes to manufacturing many tons of a drug. Thus, the current availability of single enantiomer drugs is a result of the development in recent decades of synthetic methods and separation technologies that enable the large-scale manufacture of single-enantiomer drugs. In this case study, we will discuss racemic and non-racemic drug substances by focusing on the specific examples of omeprazole, ibuprofen, ketoprofen, and naproxen.

Omeprazole and Esomeprazole

It can generally be assumed that one enantiomeric form of a drug substance will be more active at a given biological target than the other. In fact, the terms eutomer and distomer are sometimes used to describe, respectively, the “active” and “inactive” enantiomer of a racemic drug substance. Sometimes however, the situation is more complicated, as is the case with the proton pump inhibitor omeprazole. Omeprazole (marketed as Prilosec^®) was the first member of a new class of drugs intended to treat gastroesophageal reflux disease by directly inhibiting the proton pump (a H+/K+ ATPase) responsible for secreting protons (H+) into the stomach. As we noted in Section 3.10, omeprazole contains a chirality center at the tetrahedral sulfur atom and thus can exist in two enantiomeric forms (R and S). Omeprazole was originally developed and marketed as a racemic mixture and became a hugely successful product, with annual sales exceeding US$6 billion in the year 2000.

Interestingly, the R and S forms of omeprazole have equivalent inhibitory activity against the H+/K+ ATPase. This is because omeprazole itself is not the chemical species directly responsible for inhibition of the proton pump. As illustrated below (Figure 3.14), omeprazole first undergoes an acid promoted rearrangement to afford a reactive sulphenamide intermediate (some steps are omitted in the reaction scheme below). The sulphenamide intermediate next reacts with a thiol (–SH) group on the ATPase, forming a covalent disulfide bond and thereby inhibiting the enzyme (Figure 3.14).

Figure 3.14 The chiral proton pump inhibitor omeprazole is converted in the parietal cells of the stomach into an achiral sulphenamide intermediate. The sulphenamide is electrophilic and reacts with a thiol (–SH) function on the proton pump (a H+/K+ ATPase) to form a disulfide bond, thereby inhibiting the pump and slowing the secretion of protons into the stomach.

You may have noted that the sulfur atom in the active sulphenamide intermediate is no longer attached to four different substituents and is therefore no longer a chirality center. Indeed, whereas omeprazole is chiral, the active sulphenamide intermediate is not, and this explains why the R and S forms of omeprazole have equivalent activity against the ATPase (both forms are converted to the same active intermediate). One might therefore expect little or no therapeutic benefit from a single-enantiomer form of omeprazole. However, in ~3% of Caucasians and 10–15% of Asians the R and S forms of omeprazole are metabolized differently in the liver. Subsequent clinical studies comparing the R and S forms of omeprazole with the racemic mixture showed that administration of (S)-omeprazole resulted in superior drug exposure in these “slow metabolizing” individuals. Thus, while the benefit is associated with a relatively small percentage of the population, it does constitute a therapeutic benefit and esomeprazole (marketed as Nexium^®) received approval from the FDA in 2001.

Ibuprofen, Ketoprofen, and Naproxen

Next we will consider the widely used nonsteroidal anti-inflammatory drugs (NSAIDs), which include ibuprofen, ketoprofen, and naproxen among others. The anti-inflammatory, analgesic, and antipyretic properties of NSAIDs result from their inhibition of the enzyme cyclooxygenase (COX). COX enzymes are involved in the biosynthesis of prostaglandins—biological small molecules that mediate a variety of processes such as inflammation and platelet aggregation. The various members of the “profen” class bear similar structural features, as one might expect given that these drugs target the same enzyme (Figure 3.15). Each of these molecules contains an aromatic ring system attached to the alpha carbon of propanoic acid, forming a single chirality center.

Figure 3.15 The R and S forms of the common nonsteroidal anti-inflammatory (NSAID) drugs ibuprofen and ketoprofen which have been developed both as racemic mixtures and as the pure S enantiomer. The NSAID (S)-naproxen was developed only in single-enantiomer form.

Of the two enantiomeric forms of these NSAIDs, only the S form is an effective inhibitor of COX enzymes. In the case of ibuprofen however, the inactive R enantiomer is converted in the body into the active S form by a metabolic process (fortuitously, the active S form is not converted to the inactive R form). This bioconversion would seem to mitigate any advantage of a single-enantiomer form of the drug—the R form is essentially a “pro-drug” that is converted in the body into the active drug species. Another factor to consider however is the possibility of adverse drug effects that might be associated with (R)-ibuprofen prior to its conversion to the active form. As a class, NSAIDs in fact do show a relatively high incidence of adverse effects, most commonly affecting the gastrointestinal tract and less commonly but more seriously involving the liver and kidneys. It also turns out that the bioconversion of (R)-ibuprofen to (S)-ibuprofen occurs at different rates in different individuals, a not inconsequential factor given that rapid drug action is desirable in an analgesic. For these reasons, (S)-ibuprofen was developed for use in single-enantiomer form and these products are now sold in some European countries.

Unlike ibuprofen, the R form of the NSAID ketoprofen is not converted significantly into the active S form in the body. The rationale for a single-enantiomer form of ketoprofen is therefore more clear, since (R)-ketoprofen provides no particular therapeutic benefit to the patient. The active S enantiomer of ketoprofen has indeed been developed as a single-enantiomer drug (called dexketoprofen) and has the advantages of requiring a lower dose and having more rapid onset of action as compared to the racemic form.

Our final example, the NSAID naproxen, was developed from the beginning in a single-enantiomer form, (S)-naproxen, and has never been approved for use as a racemic mixture. The original manufacturing process for (S)-naproxen involved the synthesis of racemic naproxen, which was then “resolved” (separated) into its two enantiomeric forms. In this industrial process, the actual production of racemic naproxen accounted for just one-third of the total manufacturing costs, the other two-thirds were associated with the laborious separation of naproxen enantiomers. Subsequent improvements in the resolution process have reduced overall manufacturing costs significantly however.

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