JANSSEN, PAUL ADRIAAN JAN

(b. Turnhout, Belgium, 12 September 1926; d. Rome, Italy, 11 November 2003),

medicine, pharmacology, chemistry.

Janssen spearheaded research that resulted in more than eighty medicines, of which five were put on the World Health Organization’s list of essential drugs. These drugs span a broad range of therapeutic areas, including psychopharmacology, neuropharmacology, gastroenterology, cardiology, parasitology, mycology, virology, immunology, anesthesiology and analgesia.

Paul Janssen’s father, Constant, was a general practitioner. In 1934, he founded N.V. Producten Richter, a company that initially imported and sold products from the Hungarian company Richter. During and after World War II, Constant successfully developed his own products. At that time, Paul Janssen was studying classical humanities at the Jesuit college in Turnhout. Not yet seventeen years old, he enrolled at the Facultés Notre-Dame de la Paix in Namur, studying sciences at this Jesuit institution for two years. This quality, combined with the strict discipline and intensive pace of the curriculum, laid the foundations for his subsequent scientific research. At the end of 1945, he enrolled at the Faculty of Medicine at Catholic University in Leuven. By then he was already convinced that there was a relationship between the chemical structure of a molecule and its pharmacological effect. This would be the underlying principle of his research activities at Janssen Pharmceutica, the company he would one day found: the synthesis of chemical molecules to explore the relationship between their pharmacological structure and activity.

A Pharmaceutical Entrepreneur . While at the university he traveled to the United States and over a period of a few months attended summer courses in pharmacology and biochemistry at Cornell Medical School (given by Harry Gold), Harvard University (Edwin Cohn), and the University of Chicago (Carl Pfeiffer). He also visited a number of private research laboratories that were not represented in Europe at that time. A final important factor in his training as a research scientist was a stint as a part-time assistant to Nobel Prize winner Corneel Hey-mans at the State University of Ghent, where Janssen received his medical degree in 1951 (and a postdoctoral degree in pharmacology in 1956). After that he had a number of internships in Paris, Vienna, Heidelberg, and Ghent, and during his military service, he was a part-time assistant to Jozef Schuller at the Pharmacological Institute of Cologne University. In 1953, Dr. Paul, as he was familiarly called by his staff, started up his own research facility at his father’s company, which focused increasingly during the postwar years on the production and sale of products that the research unit had developed itself (AD-Vitan, Per-dolan, Rubalgan, Bronchosedal, and others). N.V. Laboratoria Pharmaceutica was founded on April 5, 1956, and Paul Janssen became the company’s managing director and research director. The expansion of the company led to the purchase of a new industrial site in Beerse, near Turnhout. Paul Janssen started there with thirty employees in new research laboratories brought under an independent company in 1958; he called them N.V. Researchlaboratoria Dr. C. Janssen in honor of his father. The company changed the location of its registered office from Turnhout to Beerse in October 1961.

Janssen’s research activities were so successful that the future of his company became a matter of concern to him in the event that anything should happen to him. Johnson & Johnson (J&J) knew about Janssen’s achievements, and William Lycan, then director of the Research Division of J&J and a member of its board of directors, paid a visit to the Beerse company. Through a share swap, the family company, with all its departments, was taken over by J&J on 24 October 24 1961. On 10 February 1964, the name of the company in Beerse became Janssen Pharmaceutica N.V.

It was a decisive step in the expansion of the international pharmaceutical strategy of J&J, and the American parent company saw the merger as an investment in Janssen’s innovative genius, an investment that subsequently proved highly lucrative; under his inspiring leadership, Janssen Pharmaceutica grew in the space of a few decades into an international company with affiliates in over forty countries.

Janssen established a production plant in China. As far back as 1978, he set up contacts with Ma Haide (whose real name was George Hatem), a doctor of Lebanese origin and one of Mao Zedong’s personal physicians, who asked Janssen to help modernize the Chinese pharmaceutical industry. In July 1981, a pharmaceutical countertrade agreement was concluded with China, the subject of which was Janssen’s anthelmintic compound, mebendazole, a product for the control of worm infections in livestock. In 1983, the Chinese launched a production plant in Hanzhong with the help of specialists from Janssen. Janssen Pharmaceutica was the first Western pharmaceutical company in the world to carry out such a large project in China. Intensive cooperation was rewarded in 1985 with a joint venture, which led to the setting up of a pharmaceutical production plant in Xian under the name Xian-Janssen Pharmaceutical Ltd. After only ten years, the turnover of this company amounted to 253 million euros, and it was acclaimed on a number of occasions as the best joint venture in the country by Fortune magazine. The most important drug produced there was Motilium, which soon passed the one billion tablet mark. As a token of the high regard in which Janssen was held, the Dr. Paul Janssen Faculty for Pharmacy was established at Xi -Jing University in China in 2002.

Between 1965 and 2000, the annual turnover of Janssen Pharmaceutica N.V. grew spectacularly. Of course, the secret of this remarkable result was due, first and foremost, to the free-ranging creativity of its exceptional founder and scientific leader. Apart from that, his success was also based on the principle of building research around people, who were inspired by his example and rewarded his trust with dedication and hard work. His research concept was also his management philosophy. It rested on four pillars: teamwork by a cross-disciplinary team within the flattest possible organizational structure; bold basic research that sought out the challenges of the unknown; feedback from practitioners; and an uncompromising commitment to freedom of thought.

In the eyes of Paul Janssen people and not investment were the key; one had to trust one’s scientists.

Research Results . As a medicinal chemist, Janssen paid particular attention to the presumed relationship—and even more so to the gaps in this relationship— between a chemical structure and the pharmacological activity of organic molecules. Discrepancies between in vitro and in vivo experiments were also a direct impetus to further investigation. This alertness to the unexpected contributed to many important discoveries. For him, it was the observable effect of a substance in a functional test model that counted. The general pharmacology with in vivo tests was the key focus of his research. The introduction of rigorously validated and standardized functional animal models is one of his most important contributions to medicinal research. Janssen’s research efforts were driven by scientific concepts. For example, as a medical student Janssen had learned about pethidine, a new drug that had been introduced into medicine in 1939. Very early on this medication seemed to cast a spell over him, perhaps because he had observed that its structure recurred in a broad class of morphinomimetic compounds, the diphenylpropylamines, and also because it had multiple medicinal properties; pethidine—it was called meperidine in the United States—had been characterized as an atropine-like antispasmodic/antidiarrheal agent, but clinically had been found to be an addictive morphinomimetic analgesic. What also interested him was the fact that pethidine was a piperidine derivative and so it would be fairly easy to iteratively synthesize analogs from it. The guiding concept was his curiosity about whether he could separate the two properties of this compound from one another, in particular its analgesic action and its antidiarrheal/antispasmodic effects. Following Dr. Paul Ehrlich he had a chemical starting point or lead compound and two bioassays for efficacy evaluation: the Straub mouse tail test for opiate activity and the electrically driven guinea pig ileum in vitro for antispasmodic activity. After synthesizing 500 analogs, he came up with eight marketable drugs.

Nonmorphine-like Analgesics . The right combination of neurolepsy and analgesia offered new possibilities for anesthetics, giving rise to fentanyl (R 4263) and a series of fentanyl derivatives, which were developed between 1974 and 1976. These drugs included sufentanil (R 33800), which in 1984, under the trade name Sufenta, made possible the first artificial human heart implant; alfentanil (R 39209) for short surgical operations; carfentanil (R 33799) for the immobilization of large animals such as elephants; and lofentanil (R 34995), which has seen stalwart service as a potent painkiller in the fight against cancer. The last two of these substances are the most powerful

analgesics in existence, exerting ten thousand times the effect of morphine. The efforts to relieve chronic pain led to the use of transdermal patches and intravenous delivery systems, thereby lowering the risk of opioid dependence. Durogesic was launched in the 1990s in the form of a patch that controls pain for seventy-two hours, without the side effects of morphine.

Neuroleptics . Until midway through the twentieth century, the treatment of psychoses left much to be desired. Then Rhône-Poulenc synthesized chloropromazine, but it had numerous unwanted effects. In 1958, however, the laboratories at Janssen developed a new chemical series of butyrophenones. The most potent molecule in this series, without any analgesic effect, but with a potent neuroleptic activity, was haloperidol (R 1625). This drug, under the trade name Haldol, eventually brought about a veritable sea change in psychiatric practice, such that straitjackets and electroshock became things of the past. Its use opened the way for psychotherapy and various types of psychosocial support, and the number of psychiatric patients in specialized hospitals in the United States fell by 80 percent from 1965 to 1988. Into the early twenty-first century, haloperidol remained on the World Health Organization’s (WHO) List of Essential Drugs.

In the 1960s, more variants were created on the same theme. Further research revealed that the antipsychotic effect of haloperidol was related to blockade of the central dopaminergic receptors. It was observed that certain analogs of haloperidol had an additional effect on the serotonergic receptors in the brain. These investigations used radioactively marked haloperidol and spiperone. More and more receptors and variants were described, and the research at Janssen made a fundamental contribution (including the identification of the serotonin-S₂ receptor). In 1982, chemists at Janssen found the first molecule that bonded specifically with the serotonin receptor; ketanserin (R41468) was a highly specific antagonist of the S₂ receptors, a potential anti-hypertensive agent, but also suitable for obtaining greater insight into the system that regulates blood pressure. Two years later the neuroleptic risperidone (R64766) came along, which combined the best qualities of haloperidol with the beneficial characteristics of ritanserin (R55667). In addition, this compound stood out for its ability to prolong slow-wave sleep and yielded good results as an add-on to Haldol therapy. It was given the trade name Risperdal and became a trailblazer for second-generation antipsychotics, improving treatment for a substantial number of patients with schizophrenia or associated symptoms. It was also found to be effective in relieving conduct disorders and psychological symptoms (depression, anxiety), so that, in particular, more elderly patients could live independently for a longer time. Next, research scientists at Janssen discovered nebivolol (R 67555). This substance, the result of a chemical application that made totally symmetrical molecules, lowers blood pressure and improves cardiac function, which was not the case with conventional β-blockers, so that the end product was better than ketanserin. It was licensed out to another company, and since the 1990s it has been marketed worldwide. In this way, the laboratories at Janssen have made an invaluable contribution to the development of neuropharmacology, which went hand in hand with discoveries in other areas of disease control.

Gastrointestinal Disorders . In 1956, diphenoxylate was discovered as an antidiarrheal agent at Janssen, but the search continued for a molecule whereby the antidiarrheal effect could be separated from the action on the central nervous system. In 1968, an attempt was made to synthesize variants of the familiar haloperidol; that led to loperamide (R 18553), which was free of morphine-like effects. Under the trade name Imodium, it became the most widely sold product worldwide for the symptomatic treatment of diarrhea, thanks to its combined mucosal and myenteric action. After a series of about one hundred molecules were synthesized in routine tests for potential neuroleptics, domperidone (R33812) was introduced to control vomiting. Due to its structure, domperidone could not cross the blood-brain barrier, but it blockaded the dopamine receptors in the stomach and intestines. The molecule was marketed under the trade name Motilium, with the indication of restoring the motility of the esophagus and the stomach. This motility is regulated by neurotransmitters that work in tandem; dopamine is the inhibitor and acetylcholine the motor. The chemists at Janssen found a starting point in clebopride, a synthetic product that acted on the dopamine receptor, and set out to make a variant that would have an action on acetylcholine. This quest led to the discovery of cisapride (R51619). Under the trade name Prepulsid, this product brought relief to millions of patients with esophageal reflux and dyspepsia. Gastrointestinal motility is therefore a major specialization at Janssen.

Worm and Fungal Infections . Health problems in the developing world played a prominent part in Janssen’s research activities. A number of veterinarians and micro-biologists returned to Belgium following Congolese independence in 1960 and were recruited by Janssen. This out-of-Africa group would play an important role in various research programs for two decades. For worm control, Janssen used an aminothiazole derivative that he had developed himself. This medicine could expel three types of nematodes from chickens but was not active in other animal species. Janssen proceeded from the hypothesis that this finding was attributable to a difference in the biotransformation of the substance by the different species of animals. Consequently, he decided to separate and finally to test all the metabolites. One of these, tetramisole, displayed a broad activity spectrum, and on this basis levamisole was developed. This drug, however, did not eliminate all parasitic worms. In 1968, researchers at Janssen Pharmaceutica discovered mebendazole (R 17635), and somewhat later flubendazole (R 17889). These benzimidazole derivatives would conquer the world under the trade names Vermox, for treatment of humans, and Telmin and Mebenvet in veterinary medicine. Levamisole and mebendazole are included in the WHO List of Essential Drugs, and are still helping to cure millions of people, in both rich and poor countries. In developing countries worm infections, as a result of the enormous protein loss that they cause, play an important role in the spiral of poverty and hunger. From research into antimycotics, researchers knew of the imidazole ring, which is present in tetramisole and levamisole. These compounds were active against (worm) parasites. Was this not a trail that might lead to a medicine effective against (fungal) parasites?

In the course of this quest, researchers found metomi-date (R 7315) and later etomidate (R 16659). Hypnomi-date remained in the early 2000s the most potent hypnotic in anesthesia. Subsequent research came up with molecules that had an antimycotic activity. Miconazole (R 14889), known by the trade name Daktarin, is used to treat fungal infections of the skin. In 1977, an elaborated variant of miconazole, namely ketoconazole (R 41400), which had a broad activity spectrum, was administered orally for the first time. Ketoconozale is the human variant of micoazole and the first antimycotic for oral use by humans. The trade name is Nizoral, a drug capable of acting on fungi in the body itself, and as such, constituted a breakthrough in antimycotic research. The most recent azole is itraconazole (R 51211), known under the trade name Sporanox, and it too is active orally. It is a safe, broad-spectrum antimycotic, with a potent action on the cytochrome P 450-enzyme in fungi and yeasts. It is effective against Aspergillus, a fungal strain often found in AIDS patients. In this case, too, the discovery resulted from skillfully varying chemical structures with the aim of obtaining a specific pharmacological effect.

An innovation in plant protection came in 1979 with propiconazole (R 49362), which was ideally suited for the protection of crops against rust. Licensed out as Tilt, this product was responsible for a 30 percent increase in grain production worldwide. Janssen also brought about a substantial improvement in the protection of materials (wood, textiles, etc.). Since 2001 the spectacular result of Janssen’s efforts in material protection is the rescue of the famous Chinese terracotta warriors in Xian from deterioration by fungi, whereby Janssen played its part in conserving a world heritage. In total, thirteen antimycotics were discovered by Janssen and his team. Levamisole, mebendazole, miconazole, and ketoconazole appear on the WHO List of Essential Drugs.

Antihistaminics for Allergies . In the 1970s, Janssen’s laboratories were turning out two to three thousand new molecules each year, usually the fruits of both a prototypal combinatorial synthesis and high throughput screening, methods that had to wait until the 1990s before coming on line in the pharmaceutical industry. In this way, researchers at Janssen came up with a variant of the cinnarizine molecule, which offered possibilities for the treatment of allergies. Oxatomide (R 35443) proved to be an effective treatment for asthma. Even more specific was the discovery in 1977 of astemizole (R 43512). This substance had a long-lasting effect on hay fever, had hardly any side effects, and in particular did not induce drowsiness. A little later levocabastine (R 50547), the world’s most potent antihistaminic, was developed. Because this medicine did cause drowsiness, Livostin (the trade name of Levocabastine) was used to treat allergic conjunctivitis.

The Human Immunodeficiency Virus . Already in 1990, Janssen stated that together with a number of colleagues, he had discovered a new class of highly effective, nontoxic substances that might be effective against AIDS. He was referring to TIBO derivatives. These were the first non-nucleoside inhibitors of the HIV-1RT (NNRTIs). However, he found them unsatisfactory and therefore started up the Center for Molecular Design (CMD) in 1996 with a view to deepening his investigations. With the aid of molecular modeling, organic chemistry, and a supercomputer, a cross-disciplinary team inspired by Janssen designed a whole series of new molecules. The affiliate Virco lent a hand in his project and focused on the development of diagnostic tests. The crystallographic studies were carried out at the Center for Advanced Biotechnology and Medicine at Rutgers University in New Brunswick, New Jersey, in the United States. This approach resulted in the identification of many promising potential drugs, including the dianilinopyrimidine (DAPY) analogs. Dapivirine is the generic name of R 147681/TMC120. It has been donated by J&J to the International Partnership for Nicrobicides (IPM) for development into an HIV-prophylactic drug. Dapivirine and Etravirine (R 165335 or TMC 125) were derived from these and were shown to be highly active in Phase I and Phase II trials. The simplicity of production of this drug makes it particularly suitable for developing countries, where the need is greatest. Janssen was the driving force behind the discovery of a new generation of anti-AIDS drugs, including rilpivirine (R278474 or TMC278), a substance characterized by an exceptional profile with respect to antiviral activity and biological availability. In Janssen’s own words, this compound is “an absolute world champion.”

Janssen was a medical and medicinal chemistry research genius, part of whose talent was his ability to gather around him the best brains in Flanders throughout the decades in which his career flourished. With more than one hundred patents to his name, he was named “the most successful drug discoverer of all time” in 2002 by Nature Reviews. Thanks to his cross-disciplinary approach, Janssen carried out research in a broad variety of therapeutic areas: mycology, psychiatry, parasitology, allergology, gastroenterology, pain control and anesthesia, veterinary medicine, and plant and material protection. His way of working was based on the relationship between the chemical structure and the pharmacological action of molecules, and the use of the appropriate experimental models to test these relationship. Janssen authored or co-authored more than 850 scientific publications and received a large number of accolades that included twenty-two honorary doctorates, five honorary professorships, and honorary memberships in more than thirty scientific institutions and organizations in his own country and beyond.

BIBLIOGRAPHY

Janssen Pharmaceutica, Beerse (Belgium) is the owner of an extensive collection of archives, a series of interviews, and company publications. A complete list of the publications of Dr. Paul Janssen is included in Niemegeers, C. J. E., ed, Historical Record of Janssen Research Publications (1952–1990). 4 Vols. Beerse: Janssen Pharmaceutica, 1992.

WORKS BY JANSSEN

With A. H. M. Jageneau, P. J. A. Demoen, C. Van de Westeringh, et al. “Compounds Related to Pethidine. I: Mannich Bases Derived from Norpethidine and Acetophenones.” Journal of Medicinal and Pharmaceutical Chemistry 1, no. 1 (1959): 105–120.

With C. Van de Westeringh, A. H. M. Jageneau, P. J. A. Demoen, et al. “Chemistry and Pharmacology of CNS Depressants Related to 4-(4-Hydroxy-4-Phenylpiperidino) Butyrophenone. Part I: Symthesis and Screening Data in Mice.” Journal of Medicinal and Pharmaceutical Chemistry 1, no. 3 (1959): 281–297.

With J. M. Van Nueten. “Difenoxine (R15403), the Active Metabolite of Diphenoxylate (R01132). Part 3: Inhibition of the Peristaltic Activity of the Guinea Pig Ileum in Vitro.” Arzneimitiel Forschung 22, no. 3 (1972): 518–520.

With R. A. Stokbroekx, J. Vandenberk, A. H. M. T. Van Heertum, et al. “Synthetic Antidiarrheal Agents. 2,2-Diphenyl-4-(4’-Aryl-4’-Hydroxypiperidino) Butyramides.” Journal of Medicinal Chemistry 16 (1973): 782–786.

With C. I. F. Niemegeers and J. L. McGuire. “Domperidone, a Novel Gastrokinetic Drug.” The Pharmacologist 20, no. 3 (1978): 209.

With D. Thienpont, J. Van Cutsem, F. Van Gerven, and J. Jeeres. “Ketoconazole: A New Broad Spectrum Orally Active Antimycotic.” Experientia 35, no. 5 (1979): 606–607.

With F. de Clerck and J. L. David. “Inhibition of 5-Hydroxytryptamine-Induced and -Amplified Human Platelet Aggregation by Ketanserin (R41468), a Selective 5-HT2-Receptor Antagonist.” Agents and Actions 12, no. 3 (1982): 388–397.

With A. Reyntjens, M. Verlinden, J. Schuurkes, and J. Van Nueten. “New Approach to Gastrointestinal Motor Dysfunction: Non-Antidopaminergic, Non-Cholinergic Stimulation with Cisapride.” Current Therapeutic Research 36, no. 5 (1984): 1029–1037.

With J. E. Leysen, W. Gommeren, A. Eens, et al. “Biochemical Profile of Risperidone, a New Antipsychotic.” Journal of Pharmacology and Experimental Therapeutics 247, no. 2 (1988): 661–670.

With L. Matthieu, P. de Doncker, G. Cauwenbergh, et al. “Itraconazole Penetrates the Nail via the Nail Matrix and the Nail Bed: An Investigation in Onychomycosis.” Clinical and Experimental Dermatology 16 (1991): 374–376.

OTHER SOURCES

Ayd, Frank J., ed. 30 Years of Janssen Research in Psychiatry.

Baltimore, MD: Ayd Medical Publications, 1989.

Healy, David, ed. The Psychopharmacologists. 2 Vols. London:

Chapman and Hall, 1996–1998.

Leysen, J., M. Borgers, R. Reneman, et al. “Belangrijkste bijdragen van Dr. Paul tot de geneeskunde en de medicinale chemie” [The Most Important Contributions of Dr. Paul to Medicine and Medicinal Chemistry]. In Dr. Paul Janssen, 1926–2003: Een portret in woorden[A Portrait in Words]. Beerse, Belgium: Janssen Pharmaceuticals, 2004.

Magiels, G. Paul Janssen: Pionier in FARMA and in China

[Pioneer in the Pharmaceutical Industry and in China]. Antwerp, Belgium: Houtekiet, 2004.

The Paul Janssen Concept of Research Management. Beerse, Belgium: Janssen Research Foundation, 1995.

Schwartz, Harry. Breakthrough: The Discovery of Modern Medicines at Janssen. Plains, NJ: Skyline Publishing Group, 1989.

Theunissen, G. Dr. Paul: De zoektocht naar betere geneesmiddelen eindigt nooit[The Quest for Better Medicines Never Ends]. Beerse, Belgium, 1992.

Roland Baetens