Fluorine in health care: Organofluorine containing blockbuster drugs

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Abstract

Organic fluorine compounds have had a profound impact on the development of bioactives for the modern pharmaceuticals market. It is estimated that up to 20% of pharmaceuticals prescribed or administered in the clinic contain a fluorine atom and 30% of the leading 30 blockbuster drugs by sales contain a fluorine. In this Highlight review, the top 10 fluorine containing pharmaceuticals (by US Sales in 2008) are highlighted. By this measure, these are currently the most significant fluorinated compounds impacting on health care. They embrace statins (Lipitor, Crestor, Vytorin, Zetia/Ezetimibe), anti-inflammatories (fluticasone propionate, Celebrex), antacids (Prevacid), antidepressants (Lexapro), neuroleptics (Risperdal) and antibiotics (Levaquin). In each case the structures and modes of action of these important drugs compounds are reviewed and representative synthetic routes are highlighted.

Graphical abstract

Organofluorine compounds have had a significant impact in the development of pharmaceutical products. The structures, modes of action and synthesis of the leading blockbuster pharmaceuticals of this class are highlighted. Currently 30% of the top thirty drugs by sales contain a fluorine atom.

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Introduction

In 1954 Fried and Sabo [1] showed that the introduction of a fluorine atom to the 9α position of cortisol, improved its therapeutic index as an anti-inflammatory by an order of magnitude. Historically the development of Fludrocortisone (Fig. 1) was the first example of the introduction of fluorine into a pharmaceuticals product. A recent review by Hagmann [2] retrospectively illustrates that over the subsequent 60 years, fluorine has been found in around 15–20% of all new chemical entities (NCIs) licensed each year for the clinical market. The element generally finds its way into the organic framework during lead optimisation studies, and particularly as a strategy to block metabolism, for example by hydroxylation enzymes, to increase lipophilicity (logP) or to tune pharmacokinetic properties [3], [4], [5]. The impact of fluorine in this context has been dramatic. Of the top 30 best selling pharmaceutical products (US Sales in 2008), 10 have at least one fluorine atom [6]. Thus 30% of the leading blockbuster pharmaceuticals contain fluorine. This Highlight profiles these compounds (Table 1) and illustrates by association the impact of organic fluorine chemistry in the development of high end of the market, health care products. The review provides some commentary on the modes of action of these leading drugs and illustrates synthetic routes, although in individual cases the actual industrial route to these compounds is not always clear (Fig. 2, Fig. 3).

Section snippets

Lipitor (Atorvastatin)

Lipitor (Atorvastatin) is currently the biggest selling pharmaceutical globally [7]. It holds the most prominent position in the blockbuster league table (Table 1) with sales of $5.9 billion ($5.9 × 109) dollars in 2008. It is commercially the most significant drug of the ‘statin’ class. The statins [8] are cholesterol lowering drugs which are prescribed to reduce the amount of biosynthetic cholesterol produced by the patient, to offset plaque accumulation and then vascular constriction with the

Fluticasone propionate

Fluticasone propionate (Table 1) is a steroidal anti-inflammatory used to treat a variety of conditions depending on how it is administered. It is a modern variant of the original Fludrocortisone (Fig. 1) reported by Fried and Sabo in 1954. Fluticasone propionate can be applied topically to treat inflammation directly associated with dermatoses and psoriasis [11]. However the major market for fluticasone propionate is to treat asthma as the most important member of a large class of inhaled

Prevacid (Lansoprazole)

Prevacid acid (Lanzoprazole) is currently the most successful commercial drug of its class in regulating gastric acid secretion (Scheme 5) [13]. Other important drugs of this group are Omeprazole, Pantoprazole and Rabeprazole, of which Pantoprazole which contains a difluoromethoxyl group (Scheme 7). They are used to treat heartburn, peptic ulcers and esophagal inflammation. Prevacid (Lansoprazole) is a representative of the ‘proton pump inhibitors’ (PPI), a group of drugs that inhibit the

Lexapro (Cipralex, Escitalopram)

Lexapro (Cipralex, Escitalopram) is an important drug for treating depression and anxiety. It is one of a large class of serotonin selective reuptake inhibitors (SSRIs) [19]. Such drugs act in the brain by blocking the reuptake of the neurotransmitter serotonin, into presynaptic cells. Lexapro is marketed in enantiomerically pure form as its (S)-enantiomer as shown. This followed from the racemic drug Citalopram which came to the end of its patent life [20]. The drug was relaunched as a single

Crestor (Rosuvastatin)

Crestor, like Lipitor (Section 2) is a statin [8]. The structural similarity to Lipitor is obvious in that both have a pendant (3R, 5R)-dihydroxycarboxylic acid residue. This moiety is important for binding to the enzyme HMG-CoA reductase, the rate limiting enzyme in cholesterol biosynthesis in humans, as described above in Scheme 1 for Lipitor. The synthesis of Crestor, like Lipitor, requires the introduction of two stereogenic centres on the (3R, 5R)-dihydroxyl carboxylic acid side chain

Zetia and Vytorin

Zetia (Ezetimibe) is a drug prescribed to lower cholesterol levels and to treat obesity [24]. It contains only Ezetimibe and is a complementary therapy to Vytorin. Vytorin is a combination therapy where Ezetimibe and Simvastatin are administered together. The combination is used to lower cholesterol levels in blood to prevent the consequent complications of atherosclerosis, heart disease and stroke. Vytorin like Zetia (Ezetimibe) also has an increasing role in the treatment of obesity.

Celebrex

Celebrex is used to treat and reduce pain associated with arthritis. It is a non-steroidal anti-inflammatory drug which inhibits prostaglandin biosynthesis. In humans it has selectivity for the inhibition of inducible cyclo-oxygenase-2 (COX-2) over cyclo-oxygenase 1 (COX-1) [31]. The COX-2 enzyme system is responsible for prostaglandin biosynthesis, the inhibition of which reduces the inflammation response [32]. More recently Celebrex is finding a role in the treatment of cancers where it

Levaquin (Levofloxacin)

Levaquin is a representative of the very large class of the fluoroquinolone antibiotics. These are probably the most successful non-natural products class of antibiotics, and it has emerged that the fluorine atom at the 9-position of the quinolone ring is essential for good antibacterial activity [33]. Many structural variants have been prepared and marketed and other significant representatives of this class are Norfloxacin, Ciprofloxacin, and Fleroxacin (Fig. 5).

Levaquin is the (S)-(−)

Risperdal (Risperidone)

Risperdal (Risperidone) is a second generation neuroleptic drug used to treat psychotic patients and predominantly to treat schizophrenia. It is also used to treat severe and manic depression and related forms of bipolar disorder. Sales in 2008 (Table 1) were a substantial increase (32%) on the 2007 sales, indicating a surge in its prescription. Risperdal (Risperidone) crosses the blood brain barrier and competes with the neurotransmitter dopamine. The drug acts by binding selectively to, and

Conclusion

This review has highlighted that a large proportion of the leading pharmaceuticals products on the global market contain organic bound fluorine. Of course the commercial fortunes of the selected drugs will rise and fall in future years, as their place in the market matures or as new compounds emerge and compete for the top rank positions. However given the prominent role of fluorine in drug development since the early 1950s, we can be sure that fluorine will continue to be an important element

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