Chiral switches lead to blockbuster drugs

Chiral switches can be used to extend the patent life of a drug or in developing new blockbusters for pharma companies. Dr Sarah Houlton highlights some of the successes and failures in this important area of chiral chemistry

The realisation that, in many cases, the different enantiomers of licensed racemic drugs have different activities has led to a rich new vein of active compounds being mined in the search for the blockbuster product.

There are five potential strategies that can be envisaged for exploiting the power of stereochemistry in drugs:

The final two of these are, however, extremely unlikely. Chiral switches have been in vogue for the past few years, and several such compounds have reached the market with improved activity and, importantly, extended patent life.

There does, however, have to be some rationale for the single isomer drug other than merely extending profits along with the patent or, indeed, for a competitor company exploiting a loophole and launching a competitor single isomer molecule. A rationale could include a reduced side-effect profile or a greatly increased efficacy.

A good example is the local anaesthetic bupivacaine(1) (AstraZeneca's Marcain), which has been used for many years, particularly as an epidural in obstetrics.

Chiroscience discovered that the L-isomer was substantially less cardiotoxic than the R-isomer, and was granted a patent for it on the basis of its lesser side-effects. It is now marketed under the trade name Chirocaine.

Such strategies are hardly innovative science, but they can at least be classified as a 'discovery'. The single isomer works — as one might expect — but it is debatable whether this is obvious or not, and a discovery needs to be non-obvious to be patentable. In the case of bupivacaine, this need for being 'non-obvious' was achieved by the lowered cardiotoxicity, which would not have been predicted before investigations began.

Despite this, in the early days of chiral switches, several single isomer molecules that might have been considered 'obvious' were granted patents in the US, although not in Europe. 'Patent examiners are human,' explained Robert Perry of law firm Gill, Jennings and Every at the 2001 CPhI conference in London last October. 'They don't always appreciate the commercial context, and these applications didn't initially strike them as odd.' The granting of a US patent to single isomer ketoprofen, an NSAID is, he believes, a good example of this.

licence wording

Perry added that another important factor in the defence against generic competition is the wording of the licence for the approved drug. For example, a company would patent a single isomer for use as an anaesthetic in obstetrics, because of its reduced side effects. However, if the wording of product licence is that the isomer is to be used in anaesthesia and obstetrics, this will preclude a generic company using this licence to launch a competitive product as an anaesthetic for any purpose during the lifetime of the single isomer's patent. It would have to apply for its own licence, specifying non-obstetric uses, ramping up the cost dramatically. 'Lots of little areas can be patented,' Perry said, 'and if you can get them into the licence, then you're protected. All you need is that peg.'

However, the background to a chiral switch is not as simplistic as one isomer being active and the other inactive. It is also possible that both could have similar activity; or the two could have a completely different activity profile. S-propranalol, for example, is a &beta:-blocker, and the R form is inactive. But with methylphenylpropyl barbituric acid, the R isomer acts as an anaesthetic, whereas the S form is a convulsant.

There are other disadvantages in using racemic mixtures as pharmaceuticals. For example, it can be difficult to monitor plasma drug levels accurately. The folic acid derivative leucovorin, used to rescue patients treated with folate antagonists, requires extremely careful monitoring. Yet only the S isomer is active and taken up by the body, leaving the R isomer alone in the plasma, making accurate monitoring nigh on impossible.

The recently launched single isomer omeprazole(2) is a good example of a chiral switch where one isomer is found to be much more active than the other. AstraZeneca's blockbusting proton pump inhibitor (PPI) was proving difficult for the company to follow up with a more active compound. Researchers at the company's labs in Sweden looked at more than 500 different molecules, with no success. Yet when they separated the isomers of omeprazole, they found that the R isomer proved more effective in inhibiting acid secretion in rats, as well as having better bioavailability. But, curiously, when trials were carried out in humans, the opposite was found — the S isomer was four times better at preventing acid secretion than the R isomer was. This difference was ultimately attributed to a liver enzyme in rats that is not present in humans.

The S isomer, now called esomeprazole, was first licensed for marketing in March 2000, and is sold under the trade name Nexium. Although it is a single isomer version of an old drug, AstraZeneca claims this is not just a simple chiral switch for patent extension purposes — it resulted from a huge clinical programme, and was the first PPI to show a significant clinical advance over omeprazole.

R to S inversion

Several NSAIDs are chiral. As well as ketoprofen(3), ibuprofen(4) has been licensed in single isomer form. The S form, dexibuprofen, is the active one but significant R to S inversion takes place in the body. So even when administered in racemic form, the drug has around 75% of the activity of the single S isomer, making a 300mg dose of the S isomer equivalent to around 400mg of the racemate.

Dilevalol (R,R-(–)-labetalol) is an example of a chiral switch that went wrong. The β-blocker with raised vasodilatory properties has two chiral centres, and the R,R diastereomer is the most active, exhibiting no chiral inversion. But alongside the increase in desired activity came a rise in hepatotoxicity.

The single isomer drug was introduced in Japan in December 1989, but was withdrawn in August 1990 as the side-effects became clear in Phase IV.

Chiral switches have one big advantage over truly de novo drug design: the chances of success are exponentially higher. The attenuation rate from traditional drug discovery routes is extremely high, with maybe 10,000 compounds yielding perhaps one launched drug, or even a couple if a company is lucky. The only real pitfalls in a chiral switch are finding that one isomer has no significant clinical advantage over the other, or that unexpected side-effects occur: there is not the huge attrition rate associated with an nce. The fact that the molecule has good activity is already known. As for a new chemical entity, a full NDA needs to be submitted to the FDA, but one advantage in production is that advanced intermediates are much more likely to be available, which will shorten the chemical development process.

Fewer clinical trials will also be needed, as the base activity is already established. But investigations into areas such as toxicology are essential — as the dilevalol case shows, there is no guarantee that increasing the desired activity will not be accompanied by a rise in an unwanted effect. Normally, the FDA requires toxicology testing on the racemate alone, even if it is the single isomer that is going to be marketed, though if anything untoward is spotted, then the isomers should be investigated separately. However, in the case of chiral switches, toxicology and pharmaco-kinetics should really be looked at for the isomer alone, as should the rate of interconversion between isomers, both in vivo and in vitro.

At the CPhI conference, David Snodin from the MCA explained some of the differences his agency requires in clinical trials between a racemate and its single isomer form. To gain a licence for a single isomer from an existing racemic drug, the pharmacodynamics would need to be investigated and compared with the original. Similarly, the kinetics would need to be looked at, and any potential for in vivo (or on shelf) chiral inversion established, and quantified. Toxicology profiles for single isomers also need to be looked at over 28 and 90 days, with the racemate as control. The number of animal trials needed for a chiral switch is lower, as much of the data have already been established.

chirally pure

A company that has been making something of a speciality of the creation of single isomer drugs is US-based Sepracor, of Marlborough, Maryland. The first of its chiral switch products to reach the market, levalbuterol, the single isomer version of albuterol/salbutamol(5), was launched in the US as Xopenox in 1999, in partnership with Abbott Laboratories.

The company has more than a dozen other compounds in development, including S-oxybutinin (based on Alza's Ditropan) for urge urinary incontinence, and R,R-formoterol (Novartis's Foradil and Yamanouchi's Atock), both of which are in Phase III. Also in Phase III are the two isomers of a metabolite of sibutramine (Abbott's antiobesity drug, marketed as Meridia in the US and Reductil in Europe), both with new indications: the R isomer for depression, and the S isomer for treating sexual dysfunction. The R form is also in Phase II for the treatment of ADHD.

Zopiclone(6) is another drug being investigated in chirally pure form by Sepracor, with the S isomer esopiclone being shown to have better tolerability, improved efficacy, faster onset and more predictable pharmacokinetics in clinical studies. The company is currently preparing the documentation for submission to the FDA. The racemate has never been registered in the US, and Sepracor has licensed the compound from its originator, Aventis.

Patents these days do not just claim the racemate, they specify the separate enantiomers or diastereomers as well to prevent loopholes being exploited by competitors, so this profitable source of potential new compounds will be short lived. However, the strategy has brought chirality to the fore, and the importance of chiral chemistry in the pharmaceutical sector has never been greater.