Chapter 31. To Market, To Market - 1998

SECTION VII. TRENDS AND PERSPECTIVES Editor: Annette M. Doherty lnsitut de Recherche Jouveinal/Parke-Davis Fresnes. France Chapter 31. To Market, To Market - 1998 Bernard Gaudilliere, lnsitut de Recherche JouveinallParke-Davis Fresnes, France In 1998, the number of new therapeutic chemical entities (NCEs) introduced into the world market for the first time was 27 (I), the fewest during the nineties. This represented a marked decrease from 39 in 1997 (2), 38 in 1996 (3), 35 in 1995 (4), 44 in the record-breaking year of 1994 (5),43 in 1993 (6), 36 in 1992 (7) and 1991 (8). However interestingly, there was a rather large number of new biological entities (NBEs) approved and launched in 1998 : among the new active substances, about one NBE could be identified for three NCEs, the tendancy for this ratio being to significantly increase from year to year. Some NBE representatives introduced in 1998 will be briefly reviewed in the last part of this introduction. With 16 NCE launches, the US was by far the most common first market for the new introductions. Switzerland was second with 4 NCEs launched, followed by Germany and Japan with 3, then Finland and Mexico with 2 new introductions. Finally, several countries, Australia, New Zealand, Netherlands, Sweden came with one NCE introduced. Regarding the originators of NCEs first launched in 1998, once again the US ranked first with 13, second trailed Germany with 5 NCEs. Japan was third with 3, then Switzerland and France with 2 each. UK and Finland came next with 1 original molecule each. One pharmaceutical company, Merck & Co. dominated with 4 NCEs originating there, followed by Pfizer, Roche and HMR with 2 each. Among the NCEs launched for the first time in 1998, several were the first in class or with a novel mechanism of action.Viagra (Sildenafil), often proclaimed as the new active molecule of the year, was introduced as an orallyactive potent inhibitor of PDE5 isozymes for the treatment of male erectile dysfunction. Vitravene (Fomivirsen) is a first-generation cytomegalovirus replication inhibitor and the only agent based on antisense technology to have obtained a marketing approval so far. Evista (Raloxifene), the first selective oestrogen receptor modulator, was launched for the prevention of postmenopausal osteoporosis. Arava (Leflunomide) was indicated for the treatment of rheumatoid arthritis, being the first and only drug indicated to date for delaying joint damage in RA. Xenical (Orlistat) is another major high profile launch of last year ; this potent inhibitor of gastrointestinal lipases prevents the absorption of dietary fat and was introduced for the long-term treatment of obesity. With the introduction of several new products, the class of agents affecting blood coagulation was one of the most active : Plavix (Clopidogrel) inhibits ADP-induced platelet aggregation and is indicated for the preventive management of secondary ischemic events in patients with established peripheral arterial disease. Aggrastat (Tirofiban) is a non peptidic antagonist of platelet GPllb/llla receptor and prevents arterial thrombosis, being indicated for patients with unstable angina. Following the withdrawal of Tasmar, the first COMT inhibitor marketed in 1997, a second one, Comtess (Entacapone) made its debut last year for the treatment of Parkinson's disease in combination with levodopa and a dopa carboxylase inhibitor. ANNUAL REPORTS

IN MEDICINAL CHEMISTRY-34

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Copynght D 1 9 9 9 by Academic Press All rights of mpmductlon in any form msemed 0065-7743/99 530 00

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and Perspectmes

The only anti-HIV introduced in 1998 was Sustiva (Efavirenz), a nonnucleoside reverse transcriptase inhibitor ; it was shown that its antiretroviral combination with two nucleosides was more effective and better tolerated than a combination using a protease inhibitor. Many new biological entities (NBEs), generally biotechnology-based products, were marketed in 1998. By way of examples, the following list of recombinant proteins can be mentioned : - Becaplermin (Chiron) : Recombinant human platalet-derived growth factor (rhPDGF) for the treatment of skin ulcers, particularly foot ulcers, in diabetic patients. - Etanercept (Immunex) : soluble recombinant human p75 TNF receptor and human lgGl Fc portion fusion protein produced in a mammalian cell expression system ; approved as a second-line agent for the treatment of rheumatoid arthritis and other inflammatory conditions, particularly those mediated by TNF. - Lepirudin (Hoechst Marion Roussel) : biosynthetic recombinant hirudin from yeast cells, slightly different from natural hirudin, acting as a highly specific direct inhibitor of thrombin ; indicated for providing anticoagulation in those patients having heparin-induced thrombocytopenia and in thromboembolic disease. Monteplase (Eisai) : modified human tissue plasminogen activator obtained by use of recombinant DNA technology ; developed and marketed for the treatment of acute myocardial infarction. - Oprelvekin (Genetics Institute) : thrombopoietic growth factor recombinant human interleukin-I 1 for use in preventing recurrent severe thrombocytopenia and reducing the need for frequent transfusions following myelosuppressive high-dose chemotherapy. - Thyrotropin Alfa (Genzyme) : recombinant human thyroid stimulating hormone for use in follow-up screening of patients who have been treated for thyroid cancer. Also, it is noteworthy that several chimeric monoclonal antibodies were launched last year : - Basiliximab (Novartis) : immunosuppressant that blocks the IL-2 receptor, a protein implicated in the proliferation of T-lymphocytes ; indicated in the prophylaxis of acute rejection episodes in renal transplant recipients. - lnfliximab (Centocor) : monoclonal antibody that blocks the activity of TNFalpha and consequently, opposes intestinal inflammation in patients with Crohn’s disease. - Palivizumab (Synagis) : humanized monoclonal antibody targeted to the F protein on the surface of respiratory syncytial virus (RSV), the leading cause of pneumonia and other severe infectious diseases in infants. - Trastuxumab (Genentech) : humanized monoclonal antibody for the treatment of epidermal growth factor receptor-2 overexpressing metastatic breast cancer.

Brinzolamide (Antiglaucoma)

(9 - 14)

Country of Origin : US

Originator : Alcon First Introduction : US Introduced by : Alcon Trade Name : Azopt CAS Registry No : 138890-62-7 Molecular Weight : 383.50

NH

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Brinzolamide was introduced as Azopt in the US for the treatment of elevated intraocular pressure (IOP) in patients with ocular hypertension or openangle glaucoma. Brinzolamide is a potent inhibitor of human carbonic anhydrase II lowering IOP after topical administration . It is the second of this class after dorzolamide (1995). Brinzolamide can be prepared in an eight-step sequence from 3-acetyl-2,5-dichlorothiophene. In patients with primary open-angle glaucoma or ocular hypertension, brinzolamide produced significant reductions in IOP and showed less ocular discomfort than dorzolamide.

Capecitabine (Antineoplastic)

(15 - 20)

Country of Origin : Switzerland Originator : Roche First Introduction : Switzerland Introduced by : Roche Trade Name : Xeloda CAS Registry No : 154661-50-9 Molecular Weight : 359.36

HO

OH

Capecitabine is a new oral fluoropyrimidine carbamate for patients with advanced neoplastic disease, approved as Xeloda for the treatment of refractory metastatic breast cancer after failure on Paclitaxel and an anthracycline-based chemotherapy regimen ; it is a prodrug of doxifluridine (5-fluorouracil ; 5-FU) activated by a cascade of 3 enzymes concentrated in human liver and cancer tissue, resulting in the selective release of 5-FU at the tumor site and offering a prolonged tumour exposure to 5-FU. Oral Capecitabine passes intact through the intestinal mucosa, is converted first by carboxylesterase to 5'-deoxy-5fluorocytidine in the liver, then by cytidine deaminase to 5'-deoxy-5-fluorouridine in the liver and tumour tissues and finally by thymidine phosphorylase to 5-FU in tumors. Therefore, Xeloda is much safer and more effective than 5-FU (for example, in the HCT116 human colon cancer and the MX-1 breast cancer xenograft.models).

Cefoselis (Antibiotic) Country of Origin : Japan Originator : Fujisawa First Introduction : Japan Introduced by : Fujisawa Trade Name : Wincef CAS Registry No : 122841-12-7 Molecular Weight : 620.63

(21 -27) /CHI

"0

HzN

OH

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and Perspectives

Cefoselis is a new fourth-generation cephalosporin and was launched in Japan as a parenteral antibiotic for a variety of infections including Staphylococcus aureus (particularly the methicillin-resistant MRSA) and Pseudornonas aeruginosa. It can be prepared in 3 related ways, all using 2pyrazolomethyl-3-cephem-4-carboxylic as the key intermediate. In preclinical studies, Cefolesis had better MIC5Os than Ceftazidime against Streptococcus pneurnoniae or Staphflococcus aureus (methicillin-sensitive MSSA or resistant MRSA) and showed significant antibacterial activity against Citrobacter and Enterobacter. Cefolesis is well tolerated in clinical studies, being eliminated mainly via glomerular filtration in humans.

Clopidogrel Hydrogensulfate (Antithrombotic) Country of Origin : France Originator : Sanofi First Introduction : US Introduced by : Sanofi, BristolMyers Squibb Trade Name : Plavix, lscover CAS Registry No : 113665-84-2 Molecular Weight : 419.89

(28 - 35)

7%

as o w 0

.H2S04

Clopidogrel was launched in the US as a potent inhibitor of platelet aggregation for the preventive management of secondary ischemic events, including MI, stroke and vascular deaths. Clopidogrel can be synthesized in 4 steps (including an optical resolution to the S active enantiomer) from 2-(2ch1orophenyl)-glycine, the key step being the cyclization to thienopyridine with formaldehyde and acetic acid. Clopidogrel belongs to the original chemical class of Ticlopidine, but shows fewer side effects (in particular, bone-marrowsuppressing effects) at the dosage generally used. Like Ticlopidine, it is an Adenosine diphosphate (ADP) antagonist acting at the purinergic P2y receptor. In in vivo experiments with rabbits, Clopidogrel shows a maximal antiaggregant effect at 20mglkg PO, reducing adhesion of platelets to the vascular subendothelium ; moreover, it reduces myointimal thickening occuring after endothelial injury of rat carotid artery. Clopigrel does not affect platelet aggregation in vitro ; actually, its in vivo activity is highly dependent on hepatic metabolism. The results of a CAPRIE trial (Clopidogrel versus Aspirin in patients at risk of ischemic events) demonstrated that Clopidogrel was well tolerated and more effective than aspirin.

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Dolasetron Mesylate (Antiemetic )

(36 - 42)

Country of Origin : Germany Originator : Hoechst Marion Roussel First Introduction : Australia Introduced by : Hoechst Marion Roussel Trade Name : Anzemet CAS Registry No : 115956-13-3 Molecular Weight : 438.49

CH,SO,H

H Dolasetron was launched as Anzemet in Australia and the US for the prevention of nausea and vomiting in chemotherapy patients. It is a highly potent and very selective antagonist of 5-HT3 receptors ; it is the sixth in this class of compounds to be marketed for the treatment of chemotherapy-inducedemesis. The last two approved in this class were Nazasetron (1994) and Ramosetron (1996). Anzemet was prepared by a seven step sequence from a cyclopentenecarboxylicester via a Robinson-Schbpf cyclisation of a dialdehyde into a key 9-azabicyclo[3.3.l]nonan-3-one. In a clinical study with 164 cancer patients treated with Dolasetron mesylate prior to Cisplatin, single doses of 1050 mg achieved major control of nausea and emesis in 73% of subjects and were well tolerated. Results from pharmacokinetic studies in humans showed that the clinical effects and duration of action seem to be due mainly to a major plasma metabolite rapidly formed and very potent itself, the (+) enantiomeric alcohol obtained by enzymatic reduction of the cyclic ketone.

Efavirenz (Antiviral for AIDS)

(43 - 48)

Country of Origin : US Originator : Merck & Co. First Introduction : US Introduced by : DuPont Pharrn. Trade Name : Sustiva CAS Registry No : 154598-52-4 Molecular Weight : 315.68

H Efavirenz was launched as Sustiva in the US for the treatment of infection by HIV, the virus causing AIDS, in combination with other anti-retroviral agents. Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI) belonging to the 3,1-benzoxazin-2-one chemical class. It is the third non-nucleoside reverse transcriptase inhibitor to have been launched to date, after Nevirapine (1996) and Delavirdine (1997), increasingthe arsenal of anti-HIV drugs for treating infected patients in dual or triple combination with nucleoside or other non-nucleoside RTls, or protease inhibitors.

Secuon W-Trends

322

and Perspectlves

Doherty, Ed

Efavirenz can be obtained by two related ways of six steps from 4-chloroaniline ; one of them is based on asymmetric synthesis by enantioselective addition of an acetylide to a trifluoroacetophenone. The anti-HIV activity of Efavirenz was demonstrated against most wild-type and clinical strains of HIV-1, including those with the most frequently observed mutations. Efavirenz has a better pharmacokinetic profile when compared with the preceding drugs of this class ; in particular, in a long-term experiment conducted in cynomolgus monkeys, Efavirenz was shown to easily cross the blood brain barrier leading to an increase of the antiviral concentration in cerebrospinal fluid.

Entacapone (Parkinson’s disease)

Country of Origin : Finland Originator : Orion Pharma First Introduction : Finland, Germany, Sweden Introduced by : Orion Pharma Trade Name : Comtess CAS Registry No : 130929-57-6 Molecular Weight : 305.29

(49 - 56)

HO

NO*

Entacapone was introduced in Finland, Germany and Sweden as an adjunctive treatment with L-dopa in Parkinson’s disease. Entacapone is the second drug in its class to reach the market; it can be obtained by basecatalyzed condensation of the corresponding benzaldehyde with a cyanoacetamide. Entacapone is a highly selective and orally-active catechol-0methyltransferase (COMT) inhibitor ; by inhibiting metabolism of L-dopa when given as an adjuvant in patients with Parkinson’s disease, Entacapone markedly prolongs the effects of L-dopa and improves its bioavailability. Results from clinical studies showed that 200mglday Entacapone coadministered with L-dopa lowered the dose of the latter required to reduce fluctuations in motor performance

Fenoldopam Mesylate (antihypertensive) (57 - 64) Country of Origin : US Originator : SmithKline Beecham First Introduction : US Introduced by : Neurex Trade Name : Corlopam CAS Registry No : 67227-57-0 Molecular Weight : 401.67

HO

HO Fenoldopam, first approved in the Netherlands in 1992, ended by reaching its first market, the US, for the short-term management of severe

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hypertension, including malignant hypertension, in the hospital setting. Fenoldopam can be prepared in 3 steps from the corresponding phenethylamine and aryloxiran, the pivotal step being the cyclisation in benzazepine in acidic medium. Fenoldopam is a potent dopamine D1 receptor agonist acting peripherally to produce systemic vasodilation.As it does not cross the bloodbrain barrier, it does not exert significant central dopaminergic activity. Fenoldopam also interacts significantly with 5HTlc and 5HT2 receptors. In comparative trials with the most common drug used for this condition in Europe, Fenoldopam was found to be appreciably more potent than nifedipine. Furthermore, Fenoldopam is fast acting and maintains a long-lasting antihypertensive effect.

Fomepizole (Antidote)

(65 - 70)

b

Country of Origin : US Originator : Orphan Medical First Introduction : US Introduced by : OrphanlCambridge Trade Name : Antizol CAS Registry No : 7554-65-6 Molecular Weight : 82.1 1

H3C

N H

Fomepizole is the first drug indicated as an antidote for ethylene glycol poisoning (it has also shown promise as a treatment for methanol poisoning). Fomepizole is 4-methyl-I H-pyrazole active as a synthetic alcohol dehydrogenase inhibitor, blocking the formation of toxic ethylene glycol metabolites which are responsible for a severe metabolic acidosis and renal failure. In limited human studies, it reversed the toxicity of potentially lethal doses of ethylene glycol. The main urinary metabolite has been reported to be 4-carboxypyrazole by oxidation of the methyl group.Compared with the current treatment (ethanol), the duration of action is longer and the safety is improved, with no toxic effects reported.

Fomivirsen Sodium ( antiviral, treatment of CMV retinitis)

(71 - 78)

Introduced by : Ciba Vision Country of Origin : US Originator : lsis Pharmaceuticals Trade Name : Vitravene CAS Registry No : 160369-77-7 First Introduction : US

Fomivirsen Sodium was launched as Vitravene in the US and is indicated for the local treatment of cytomegalovirus (CMV)-induced retinitis in AIDS patients. It consists of a phosphorothioate oligonucleotide (PS) comprised of a sequence of 21 nucleotides. Fomivirsen is synthesized using solid-phase phosphoramidite chemistry. Fomivirsen inhibits human CMV replication by a antisense mechanism : it targets an immediate early mRNA of cytomegalovirus, inhibiting the expression of two regulatory proteins. Fomivirsen was the most advanced first-generation PS drug candidate in human clinical trials and was the first agent based on antisense technology to reach the market. In normal human dermal fibroblast cells, Fomivirsen inhibited AD169 human CMV replication by more than 90%, at a concentration of 5pM ; it showed greater hCMV replication inhibitor properties than ganciclovir in several experimental models.

Section W-Trends

324

Leflunomide (Antiarthritic)

Doherty, Ed

and Perspectlves

(79 - 88)

Country of Origin : Germany Originator : Hoechst MarionRoussel First Introduction : US Introduced by : Hoechst Marion Roussel Trade Name : Arava CAS Registry No : 75706-12-6 Molecular Weight : 216.24

Leflunomide is an orally-available disease-modifyingantirheumatic drug and was launched as Arava in the US for the treatment of rheumatoid arthritis (RA) ; it is the first and only drug to be indicated to slow down structural joint damage of RA, so addressing an unmet medical need. Leflunomide is prepared in 3 steps from the appropriate acetoacetic anilide using a nitrile oxide- enamine cycloaddition reaction to assemble the isoxazole ring. Leflunomide is a prodrug, being extensively metabolized in vivo into the corresponding 2-cyano-3-hydroxy-2-butenamide resulting from fragmentation of the isoxazole ring. This cyanoenol is actually the active metabolite and several experiments in animals have demonstrated that after oral administration, substantial and sustained levels of this metabolite were delivered to the systemic circulation. In vitro, Leflunomide’s active metabolite inhibits dihydroorotate dehydrogenase, an enzyme involved in the biosynthesis of pyrimidine nucleotides, probably accounting for its immunosuppressive effect in vivo. Other mechanisms of action such as inhibition of tyrosine kinase and inhibition of responsiveness to interleukin-2 have been proposed. In diverse models of autoimmune or allergic diseases, Leflunornideshowed efficacy both prophylactically and therapeutically.

Loteprednol Etabonate (Ophthalmic antiinflammatory, antiallergic)

(89 - 94)

Country of Origin : US Originator : Pharmos First Introduction : US Introduced by : Bausch & Lomb Trade Name : Lotemax (0.5%) ; All

CI

(0.2%)

CAS Registry No : 08203446-6 Molecular Weight : 466.96

0 Loteprednol etabonate was introduced in the US as Lotemax (opththalmic suspension at 0.5%) for the treatment of steroid-responsive inflammatory conditions of the palpebral and bulbar conjunctiva, cornea and anterior segment of the ocular globe, and as Alrex (opththalmic suspension at 0.2%) for the symptomatic treatment of seasonal allergic conjunctivitis. Loteprednol etabonate is a novel soft corticosteroid with a superior efficacy and an improved safety profile compared to prior ophthalmic steroids due to its

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metabolic lability and a fast enzymatic transformation to inactive metabolite. A combination of Lotemax with the antibiotic Tobramycin is currently under development.

Miglitol (Antidiabetic)

(95 - 102)

Country of Origin : Germany Originator : Bayer First Introduction : Germany Introduced by : Sanofi Trade Name : Diastabol CAS Registry No : 72432-03-2 Molecular Weight : 207.23

Miglitol was introduced last year in Germany as an auxiliary treatment for non-insulin dependent diabetes (NIDDM). A simple two-step synthesis of Miglitol consists of converting 6-desoxy-6-aminosorbose into desoxynojirimycin by reductive cyclization, then selectively hydroxyethylating the cyclic nitrogen. Miglitol is a short-acting intestinal alpha-D-glucosidase inhibitor, reducing postprandial glucose excursions by helping to delay absorption of complex carbohydrates. Acarbose and voglibose are the previous compounds marketed in this class. At low doses, orally administered miglitol was shown to be rapidly and completely absorbed then removed by renal excretion.

Mizolastine (Antihistaminic)

(103 - 108)

Country of Origin : France Originator : Synthelabo First Introduction : Germany, Switzerland Introduced by : Galderma Trade Name : Mizollen CAS Registry No : 108612-45-9 Molecular Weight : 432.50

\

F

Mizolastine was marketed in Germany and Switzerland as Mizollen for the symptomatic relief of seasonal and perennial allergic rhinoconjunctivitis and urticaria. Mizolastine is a new long-acting, orally active antihistaminic agent with a rapid onset of action ; the two most recent H I antagonists launched were fexofenadine, metabolite of terfenadine (Sepracor, 1996) and Olopatadine (Kyowa Hakko, 1997). Mizolastine can be prepared in 2 steps from 2-chloro 1(4-fluorobenzyl)benzimidazole by successive condensations of appropriate

326

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and Perspectlves

Doherty, Ed.

amine and thioether. Mizolastine selectively blocks the peripheral H I receptors (but not the serotonergic, noradrenergic, muscarinic receptors) with a minimal occupancy of brain receptors, and therefore does not elicit any sedative effects. Moreover, Mizolastine does not produce cardiac rhythm disorders which have been associated with certain non-sedating antihistamines in humans. Montelukast Sodium (Antiasthma)

(109 - 116)

Country of Origin : US Originator : Merck & Co First Introduction : Finland, Mexico Introduced by : Merck & Co Trade Name : Singulair CAS Registry No : 151767-02-1 Molecular Weight : 608.17

Montelukast was launched as Singulair in Mexico and Finland for the management of mild to moderate asthma inadequately controlled by inhaled corticosteroids and short-acting beta2-agonists. Montelukast can be obtained by an seven-step synthesis from 3-[2(E)-(7-chloroquinolin-2-yl)vinyl] benzaldehyde. Montelukast is a potent, selective and orally active antagonist of the CysLTl (formerly called LTD4) receptor, thus blocking the effects of the cysteinyl leukotrienes LTC4, LTD4 and LTE4 on microvascular permeability and the activation of eosinophils. Montelukast represents the third molecule of this class which has been approved in asthma after pranlukast (1995) and zafirlukast (1996). Montelukast has been studied extensively in placebo-controlled clinical trials, in mildly or severe asthmatic patients challenged with LTD4 or exercise. A variety of acute bronchoconstricting challenges were inhibited or attenuated with all doses used. Montelukast demonstrated clinically significant improvements in the parameters of asthma control associated with an appreciable improvement in quality of life., reducing days with asthma exacerbations and allowing significant tapering of corticosteroids. Montelukast is well-tolerated and only needs to be administered once a day.

Mosapride Citrate (gastroprokinetic)

Country of Origin : Japan Originator : Dainippon First Introduction : Japan Introduced by : Dainippon Trade Name : Gasmotin CAS Registry No : 11288541-3 Molecular Weight : 614.05

(117 - 124)

9

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Mosapride citrate, a new gastroprokinetic benzamide was introduced in Japan as Gasmotin for the relief of gastrointestinal symptoms in patients with chronic gastritis, gastro-oesophageal reflux, dyspepsia and post-surgery use. Mosapride is synthesized by final amidation between the corresponding benzoic acid, itself obtained in 3 steps from methyl 4-acetamido salicylate, and the appropriate 2-aminomethyl-morpholine. Mosapride is a 5-HT4 partial agonist without notable activity for D2,5-HTI , 5-HT2, alpha-I and alpha-2 receptors. In dogs, mosapride was as potent as cisapride to stimulate antral and duodenal motility. In most of species including man, mosapride undergoes extensive cleavage to a N-debenzylated metabolite which retains partial 5-HT4 activity but has potent 5-HT3 antagonist activity. Orlistat (Antiobesity)

(125 - 132)

I

Country of Origin : Switzerland First Originator Introduction : Roche: New Zealand Introduced by : Roche Trade Name : Xenical CAS Registry No : 096829-58-2 Molecular Weight : 495.74

CHhCH,

H , C \ /\/Cd

O

b

o

P

H

0

H,C C",

Orlistat was launched in the UK as Xenical for the long-term treatment of obesity, preferably in conjunction with a moderately reduced calorie diet. Orlistat is a tetrahydro-derivative of the natural hypolipaemic lipstatin (from Streptomyces toxyfncini) and can be obtained either by hydrogenation of lipstatine or by several different synthetic ways involving many steps from ( S ) rnalic acid. Orlistat is a potent inhibitor of gastrointestinal lipases required for the lipolysis and digestion of dietary fat, in particular of pancreatic lipase ; as a result, it prevents the absorption of about one third of the fat contained in food and acts as an effective weight-reducing therapy. The outcomes of several clinical trials involving thousands of obese patients showed that Orlistat promotes a significant weight loss (often between 5 and 10% after one year) and improves cardiovascular risk factors such as total cholesterol, LDUHDL ratio, blood glucose levels, insulin, blood pressure. Orlistat has minimal systemic absorption, the majority of the compound itself being recovered in the feces ; it does not affect other gastrointestinal processes, or the absorption of other rnacronutrients such as carbohydratesand proteins. Paricalcitol (vitamin D) Country of Origin : US Originator : Abbott First Introduction : US Introduced by : Abbott Trade Name : Zemplar CAS Registry No : 131918-61-1 Molecular Weight : 416.65

(133- 139)

328

Section VD-Trends

and Perspectives

Doherty, Ed

Paricalcitol was launched as Zemplar in the US for the prevention and treatment of secondary hyperthyroidism associated with chronic renal failure. Paricalcitol is a synthetic vitamin D2, namely a novel 1-alpha-hydroxy-I9-noranalogue in which the ring A exocyclic methylene group, typical of all vitamin D systems, has been replaced by two hydrogen atoms. Paricalcitol is the first vitamin D analogue marketed for this indication. In patients with chronic renal failure, Paricalcitol appreciably reduced levels of parathyroid hormone (PTH) without a significant difference in the incidence rate for hypercalcemia or hyperphosphatemia when compared with placebo. Rabeprazole Sodium (Gastric antisecretory) Country of Origin : Japan Originator : Eisai First Introduction : Japan Introduced by : Eisai Trade Name : Pariet CAS Registry No : 117976-90-6 Molecular Weight : 381.42

(140 - 147)

*& Na

Rabeprazole was launched as Pariet in Japan, its first market, for the treatment of peptic ulcers including gastric and duodenal ulcers. From 4-chloro2,3-dimethylpyridine N-oxide, a six step synthesis allows access to the basic skeleton after successive condensations. Rabeprazole, a structural analog of Omeprazole, the first compound to have been marketed in this class up to now, is reported to be a more potent inhibitor of gastric H+/K+-adenosinetriphosphate (ATPase) ; a common mechanism of action of this chemical class involves the conversion at low pH to a reactive sulphonamide that itself binds to cysteine residues located on the enzyme. Moreover, rabeprazole showed an antibacterial activity against Helicobacter Pylori, with a MIC90 of 1.56 pg/ml. Rabeprazole has a faster onset of action compared with omeprazole, but a shorter duration of action, being extensively and rapidly metabolized in several animal species. In clinical studies in patients with gastric ulcers, 10 and 20 mg rabeprazole sodium once-daily significantly inhibited basal and stimulated acid output. Rabeprazole is awaiting registration in the US for treatment of gastrooesophageal reflux disease (GORD) and other pathologic hypersecretory conditions including Zollinger-Ellison syndrome.

Raloxifene Hydrochloride (Osteoporosis) Country of Origin : US Originator : Lilly First Introduction : US Introduced by : Lilly Trade Name : Evista CAS Registry No : 82640-04-8 Molecular Weight : 510.05

(148 - 154)

/

OH

Chap. 31

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Gaudilliere

Raloxifene was launched as Evista in the US for the prevention of postmenopausal osteoporosis. It is noteworthy that this molecule was formerly under development as keoxifene for breast cancer and prostatic hypertrophy. Raloxifene can be prepared by acylation of 6-methoxy-2-(4-methoxyphenyl) benzothiophene followed by simultaneous demethylation of both methoxy groups. Raloxifen is a selective estrogen receptor modulator, exerting antiestrogenic action on certain tissues (breast) and also estrogenic action on bone metabolism or serum lipids. In normal early postmenopausal women, 200 mg daily produced a trend towards suppression of estrogen effects. Raloxifen impeded bone loss in osteoporosis. A two-year study in postmenopausalwomen with an increased risk for osteoporosis showed that Raloxifen markedly prevented non-traumatic vertebral fractures. Results of several clinical studies demonstrated that Raloxifen appreciably reduced the risk of developing breast cancer. Moreover, it had favourable effect on lipid profiles without having the potential side-effects of estrogen-based therapies. Several extensions for different uses of this molecule are planned, for example growth disorder, obesity, colon tumor and skin atrophy. No serious drug-related events have been reported in the limited number of clinical trials.

Repaglinide (Antidiabetic)

(155- 163)

Country of Origin : Germany Originator : Boehringer lngelheim First Introduction : US Introduced by : Novo Nordisk & Schering Plough Trade Name : Prandin CAS Registry No : 135062-02-1 Molecular Weight : 452.59

Repaglinide was marketed in the US as an orally active hypoglycemic agent in patients with a type II diabetes mellitus, to lower blood glucose in synergistic combination with metformin, when hyperglycemia cannot be controlled by diet, exercise or metformin alone. Chiral (S)-repaglinide can be synthesized in several ways, each involving a stereoselective reduction of an imine or enamine group. Repaglinide is a nonsulfonylurea belonging to the meglitinide family, with an insulin-releasing effect mediated by pancreatic betacells, by closing the ATP-sensitive K+ channels that, in turn, increases the cytosolic concentration of Ca++. In several animal models, repaglinide was more efficient than glibenclamide as a dose-dependant promoter of insulin release, but its mechanism of action is probably slightly different. Repaglinide has a rapid onset of action, a short duration of action and a reduced risk of hypoglycemia compared to glyburide.

Section W-Trends

Risedronate Sodium (Osteoporosis)

Dohefly, Ed.

and Perspectives

(164 - 169)

Country of Origin : US Originator : Procter Gamble First Introduction : US Introduced by : Procter Gamble & HMR Trade Name : Actonel CAS Registry No : 115436-72-1 Molecular Weight : 305.10

Risedronate sodium was launched as Actonel in the US for treatment of Paget's disease. Risedronic acid is readily obtained by condensation of 2-(3pyridy1)acetic acid with phosphorous acid in presence of phosphorus oxychloride. Risedronate sodium is an orally active bisphosphonate of third generation, showing more potent bone antiresorptive properties than most of prior bisphosphonates like etidronate which has been used for the same indication since 1978. The biological mechanism by which Risedronate, and generally bisphosphonates, act is not quite clear presently ; recent advances have suggested that aminobisphosphonates interfere with the HMG-CoA pathway and inhibit protein prenylation, causing apoptosis of osteoclasts and macrophages. These apoptotic effects are correlated to the anti-resorptive properties of this class of compounds. In a 2 month clinical trial involving patients with Paget's desease, 30 mg risedronate daily achieved an appreciable reduction of serum alkaline phosphatase levels, an indicator of bone stabilization, in 77% of patients, compared with 11% on etidronate at 400 mg daily for 6 months. Risedronate is also in development for the treatment and prevention of various bone diseases, particularly post-menopausal and corticosteroid-inducedosteoporosis.

Rizatriptan Benzoate (Antimigraine) Country of Origin : US Originator : Merck & Co First Introduction : Mexico Introduced by : Merck & Co Trade Name : Maxalt CAS Registry No : 145202-66-0 Molecular Weight : 391.47

(170 - 177)

H

Rizatriptan was launched for the first time as Maxalt in Mexico for the acute treatment of migraine headaches with or without aura in adults. It is the third in a new generation of triptan migraine drugs to challenge the firstgeneration product Sumatriptan from Glaxo Wellcome, after Zolmitriptan (Zeneca) and Naratriptan (Glaxo Wellcome). It can be synthetically obtained by two related routes having respectively 3 and 4 steps, both starting from 1-(4-aminobenzyl)-l,2,4-triazole. Rizatriptan is a full 5HTI DI1B receptor agonist retaining a significant affinity at 5-HT1A sites (plC50 = 6.4), with a low affinity for nond-HT sites. It shows craniovascufar selectivity for human isolated middle meningeal over coronary arteries ; its effect on coronary artery constriction is significantly less than that for Sumatriptan. Rizatriptan inhibits the release of neuropeptides that cause swelling of cranial blood vessels. Rizatriptan has a good oral bioavailability (64% and 47% in rats and dogs respectively). and a rapid onset of action : the headache relief in

Chap. 31

To Market, To Market-1998

Gaudilliere 331

human occurs within 30 to 45 minutes of taking 20 mg. It also relieved nausea and hypersensitivity to noise (phonophobia) and light (photophobia) that are often symptoms accompanying a migraine attack. Among at least 6 metabolites identified in humans after a single oral dose (60 mg), the major urinary metabolite was the corresponding indole-3-acetic acid. Maxalt is available as a novel oral formulation of rapidly dissolving tablets or wafers that does not require liquid for ingestion.

Sibutramine (Antiobesity) Country of Origin : Germany Originator : Knoll First Introduction : US Introduced by : Knoll Trade Name : Meridia, Reductil GAS Registry No : 125494-59-9 Molecular Weight : 334.33

(178 - 186)

CI

.eC;:.

CH3 H3

/

.HCI

CH3

Sibutramine was introduced as Meridia in the US for the control of obesity, in conjunction with a reduced-calorie diet. Sibutramine can be prepared in four steps from 4-chlorobenzyl cyanide. Sibutramine acts as a serotonin and noradrenaline reuptake inhibitor ; in animal studies, it reduces energy intake by creating a satieted feeling and increases energy expenditure by enhancing thermogenesis. In a clinical study in obese patients treated with 10 or 15 mg of Sibutramine once-daily, meaningful weight loss was sustained for 12 months ; an additional study demonstrated a lack of abuse potential. An appreciable part of Sibutramine's effect would also be due to its 2N-mono and didesmethylmetabolites, which are very potent monoamine reuptake inhibitors themselves.

Sildenafil Citrate (Male Sexual Dysfunction)

((187 - 194)

Country of Origin : UK Originator : Pfizer First Introduction : US Introduced by : Pfizer Trade Name : Viagra CAS Registry No : 139755-83-2 Molecular Weight : 474.58

?\ N, J

rNICH' COOH

0

CY

nooc

Sildenafil was launched as Viagra in the US for the treatment of organic orland psychological male erectile dysfunction (ED). Sildenafil can be obtained by functional rearrangement of the corresponding 5-aryl 1,3-dialkyl pyrazolo[4,3d]pyrimidin-7-one, itself synthesized in a seven-step sequence from a pyrazole5-carboxylate. Sildenafil is a potent and selective inhibitor of type V cGMP phosphodiesterases (PDE5) ; IC50 = 3nM on isozymes from human corpus cavernosum tissue. This orally-active therapy is completely new and presents advantages over the classically recommended options such as vacuum

332

Secbon W-Trends

Doherty, Ed

and Perspectlves

constriction devices, drug injection or prosthesis implantation ; for these reasons, this first drug is likely to have a large acceptance fot the treatment of male ED. In experiments with incubated rabbit penile tissue, Sildenafil was shown to cause accumulation of cGMP. By inhibiting the enzyme PDE5, the predominant isozyme in the corpus cavernosum, Sildenafil induces an elevation of levels of second messager cGMP, which is involved in the regulation of vascular tone ; it was suggested that the specific elevation of cGMP due to Sildefanil would mediate an enhancement of nitric oxide-dependent relaxation of corpus cavernosal tissue. Several clinical studies using 10-100 mg Sildenafil have confirmed a good effectiveness and tolerability in healthy males. New trials in women with sexual disfunction have been initiated and positive results could enlarge the potential market of this drug.

Tirofiban Hydrochloride (Antithrom botic)

(195 - 202)

Country of Origin : US Originator First Introduction : Merck: & Switzerland Co and the US Introduced by : Merck & Co Trade Name : Aggrastat CAS Registry No : 142373-60-2 Molecular Weight : 477.06

"

L

o

e

0 H N ; 7H, y C " , 0 0

HCI

Tirofiban was launched as Aggrastat in Switzerland and the US for patients with unstable angina or non-Q-wave myocardial infarction to prevent cardiac ischemic events. Tirofiban is synthesized from (S)-tyrosine by a fourstep process. Tirofiban is a novel highly potent antiplatelet agent that inhibits the interaction of fibrinogen with GPllb/llla, an activated platelet membrane-bound glycoprotein complex. It prevents arterial thrombus formation in a dosedependent manner. Clinical efficacy was highly significant with an absolute and relative risk reduction. In these studies, treatment with tirofiban was well tolerated, without significant adverse effects. Trovafloxacin Mesylate (Antibiotic) Country of Origin : US Originator : Pfizer First Introduction : Switzerland and the US Introduced by : Pfizer Trade Name : Trovan CAS Registry No : 157605-25-9 Molecular Weight : 512.47

((203 - 210)

CH,SO,H H,N"'

.,., F

Trovafloxacine mesylate, a new fluoroquinolone, was launched in Switzerland and the US, in both oral (rlovan) and iv (alatrofloxacin, N-Ala-Ala substituted prodrug of trovafloxacin) formulations for adult use as broad-

Chap. 31

To Market, To Market-1998

Gaudilliefe

333

spectrum antibiotic agent in diverse acute bacterial infections, particularly community-acquired respiratory infections (ie nocosomial pneumonia). In a clinical study of acute exacerbations of chronic bronchitis, trovafloxacin at 100 or 200 mg daily demonstrated advantages over amoxicillin, cephalosporins and clarithromycin. A favorable pharmacokinetic profile allows only once a day dosingI.

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55.

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