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Breakthrough: The Discovery of Modern Medicines at Janssen
The Discovery of Modern Medicines at Janssen
181 pages, Hardcover
First published January 1, 1989
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March 30, 2024
Notes
“70 new pharmaceuticals over a span of 36years...Paul Janseen and his research team at Beerse, Belgium. Five of these compounds are on the ‘essential drug’...WHO” (foreword)
Chapter 1 Molecules to Medicine
“A rule of thumb...1/10k compounds synthesized by medical chemists ever prove to be useful. At a highly productive firm...ratio is...approximately 1/1000” (6)
“At Janssen, the first human beings who receive a new drug are frequently the staff members who have been most involved with this particular compound.” (10)
Paul Jannsen’s dad did marketing / Belgian work for the pharma company founded by Gordon Richter (Jewish guy); Paul janssen went to Jesuit school, was an excellent student and chess player; goes to Medical school, realizes the patnet medicines his dad is selling are mostly bullshit; goes to America for a tour of pharma and supports himself by betting on his chess games (!);
Paul Janssen is 26 when he opens a research laboratory, his dad gives him a loan of about 5k in today’s money;
“In 1952, I was literally ignorant. I didn’t know much about medicine, chemistry, or pharmacology. But in 1953, virtually everything was possible because the field was new. It was relatively easy to find new drugs. ” (24)
Early office practice: “Jansse practiced an open-door policy, making himself accessible to any researcher...could come directly to me if he had something to report...point to visit every laboratory at least once daily...to ask...”what’s new?”...ambition was to keep on top of all research, to spot promising developments early, and to assign additional researchers to work on these developments. ” (27)
Hard-working: “thought nothing of working 6 days a week from 6AM until midnight. At first, he expected his employees to do the same...marriages were threatened...with joy that they learned [he] had gotten engaged...once he got married, he left work by 7PM, and so we could, too.” (28)
The 1960’s mark the era of requiring more evidence, especially on efficacy. Prior to that, you checked safety, and then effectively got by with anecdotal evidence.
Their move into China is in 1983, but they become interested in the late 1970s: “technical cooperation between the Hanjiang Pharmaceutical factory and Janssen Pharmaceutica...help its partner build a chemical plant that would produce the raw material for Vermox. Janssen specialists would design the plant, assure that it had all the necessary pollution controls, provide the needed machinery, and train Chinese workers...very good theoretical backgrounds...lack..practical experience...very dedicated, and very fast learners....most of the dealings with the government...can be left to the Chinese partners, who are likely to be much more effective than a foreign group acting alone. ” (45-46)
Ring of Success Chapter 4
The story of H2 blockers: Dr. james Black theorized that ulcers were caused by + gastric acid secretion; that this secretion was controlled by histamines; theorizes that there are H1 AND H2 receptors (former had been known because of anti-allergy medications); Smith Kline and French spend 1963-1970s trying to find a H2 blocker - Tagemet - but “it must be stressed that...Black and his collaborators started the search with no certainty that an H2 receptors existed, let alone an H2 inhibitor....took almost a decade. (51-53)
Besides starting with biological molecules and making synthetic equivalents, you can also try varying the effects of existing drugs or molecules and narrowing their specificity. This is how they found variations on morphine for anesthesia, analgesia, and antidiarrheal drugs.
A piperidine ring is found in haloperidol, fentanyl, Remivox, and loperamide - its funny fentanyl is mostly considered a “potent anaesthtic” (54) - but with variations of different carbon rings, functional groups like hydroxyl, methl,
Question: how much does structural optimization typically improve drug effects? Is it orders of magnitude? In antibodies I think its often a few orders of magnitude improvement - in organic chem, how much is it?
“Before computers were readily available...Dr. Janssen created an analogy computing system for recording every bit of information, chemical and biological, that was gathered about his compounds.” (58)
Chapter 5 Changing the Face of Psychiatry
Pre-1950’s basically no drugs were available for schizophrenia - then reserpine, then Thorazine, Haldol
Recognition of de-institutionalization and its downsides: “the new nati psychotic drugs were responsible for an economic and social revolution....medicines made it possible for many mentall yill people to end their antisocial behavior, to behave normally in family life, and to hold jobs...methods of caring...came to be questioned...release of large numbers of psychotic patients...this was often not the case..many psychotic individuals have become part of the large population of the urban homeless” (62)
Animal models for psychiatry (!): seminal paper - “could produce catalepsy in rats...protect rats from normally lethal injections of....norepinephrine...inhibit altogether certain types of learned and condition reflexes...prevent dogs which have received...apomorphine...from vomiting.” (63)
Q: what gems were recreational or nootropic use are buried in pharmaceutical company archives? Not selective enough for pharmaceutical use or good animal model for cognition
“Fluorine and chlorine...share the common property of impeding a compound’s rapid metabolic breakdown in the body”
Haldol trials: “both recalled the amazing transformation of the psychiatric ward...usual disorderly, noisy ward was transformed through the calming effects of Haldol...some simply could not believe that such a radical transformation of their psychotic patients could be obtained merely by administering a drug...” (69)
Obvious but important research spillovers to basic science with radioactively-labeled derivatives of Haldol
Pipamperone: “improves sleep...antiautistic, disinhibiting, and resocializing”
Ritanserin: “extraordinary effects on human sleep...increasing the duration of slow-wave sleep” (80)
In the Conquest of Pain Chapter 6
Already interest in ways to reduce abuse potential of opiates (!)
Chapter 7 Pioneers Against Parasitic Disease
Dr. Robert marsbroom was a Belgian scientist who had spent many years in the Belgian Congo (pre-Independence) and comes to Jannsen after its independence; gets put to work on anti-parasitic medications. Dr. Marsbroom eventually bring onboard a number of top parasite specialists who previously worked in those colonies.
“Guided by his intuition, Dr. Janssen was convinced that the core...would be heterocyclic...it looked as if we were climbing trees to seek fish....after testing 2,721 compounds without any luck....R 6438 showed the desired activity in chickens. ” (100) but it only works in chickens because it was probably a prodrug...that takes a long time to sort out, then there’s an isomer issue, then finally levamisole is the result.
Some unexpected good side effects from levamisole: “apparent cures of herpes-like viral infections in ruminants and monkeys..calves and pigs...suddenly regained normal weight...tended to strengthen the immune systems...some patients whose cancers went into remission.” colon cancer adjuvant treatment
Chapter 8 Waging War Against Fungal Disease
(111) mentions of antibiotic overuse, patients on chemotherapy getting fungal infections,
Chapter 9
One of the original space drugs was diphenoxylate: “Dr. Charles Berry...medical chief of the US astronaut program...assist in avoiding inflight defecation when necessary.” (130)
Chapter 10 New Hope for Digestive Disorders
After 20 years of only a single GI drug, Janssen pushes for more GI drugs. Dr. Reyntjens looks into trying to find anti-nausea drugs that don’t have CNS effects.
Chemoreceptor trigger zone is not protected by blood brain barrier
Domperidone was developed but weirdly not really available in the US (?); Cisapride was too but is a little risky because of cardiac side-effects.
Chapter 11 Don’t Surrender to Allergies
“”...some Signs that flunarizine may improve the ability of a patient suffering from cerebrovascular diseases to think logically. As a result, flunarizine is used widely to improve mental functioning in the elderly.” (149)
Chapter 12 The Crusade for Animal and Plant Health
“Sabeluzole...cognition enhancer that increases the blood flow to organs and tissues. Impaired memory in the elderly is improved after only a single dose. ” (172)
“The hallmark of scientific research today...is the increasing rate and pace of change...51 years between 1830 and 1881, before...Faraday’s findings...until the first practical electrical generator...40 years before...E=Mc2...until the first atomic bomb...20 years...DNA...1971 transplanted genes from one organism to another...1957, Leo Isocki...electrons can tunnel...six years later...semiconductor diodes...Dr. Frank Press, President of the National Academy of Sciences, suggests that were are in the Golden Age of Science.” (175)
“70 new pharmaceuticals over a span of 36years...Paul Janseen and his research team at Beerse, Belgium. Five of these compounds are on the ‘essential drug’...WHO” (foreword)
Chapter 1 Molecules to Medicine
“A rule of thumb...1/10k compounds synthesized by medical chemists ever prove to be useful. At a highly productive firm...ratio is...approximately 1/1000” (6)
“At Janssen, the first human beings who receive a new drug are frequently the staff members who have been most involved with this particular compound.” (10)
Paul Jannsen’s dad did marketing / Belgian work for the pharma company founded by Gordon Richter (Jewish guy); Paul janssen went to Jesuit school, was an excellent student and chess player; goes to Medical school, realizes the patnet medicines his dad is selling are mostly bullshit; goes to America for a tour of pharma and supports himself by betting on his chess games (!);
Paul Janssen is 26 when he opens a research laboratory, his dad gives him a loan of about 5k in today’s money;
“In 1952, I was literally ignorant. I didn’t know much about medicine, chemistry, or pharmacology. But in 1953, virtually everything was possible because the field was new. It was relatively easy to find new drugs. ” (24)
Early office practice: “Jansse practiced an open-door policy, making himself accessible to any researcher...could come directly to me if he had something to report...point to visit every laboratory at least once daily...to ask...”what’s new?”...ambition was to keep on top of all research, to spot promising developments early, and to assign additional researchers to work on these developments. ” (27)
Hard-working: “thought nothing of working 6 days a week from 6AM until midnight. At first, he expected his employees to do the same...marriages were threatened...with joy that they learned [he] had gotten engaged...once he got married, he left work by 7PM, and so we could, too.” (28)
The 1960’s mark the era of requiring more evidence, especially on efficacy. Prior to that, you checked safety, and then effectively got by with anecdotal evidence.
Their move into China is in 1983, but they become interested in the late 1970s: “technical cooperation between the Hanjiang Pharmaceutical factory and Janssen Pharmaceutica...help its partner build a chemical plant that would produce the raw material for Vermox. Janssen specialists would design the plant, assure that it had all the necessary pollution controls, provide the needed machinery, and train Chinese workers...very good theoretical backgrounds...lack..practical experience...very dedicated, and very fast learners....most of the dealings with the government...can be left to the Chinese partners, who are likely to be much more effective than a foreign group acting alone. ” (45-46)
Ring of Success Chapter 4
The story of H2 blockers: Dr. james Black theorized that ulcers were caused by + gastric acid secretion; that this secretion was controlled by histamines; theorizes that there are H1 AND H2 receptors (former had been known because of anti-allergy medications); Smith Kline and French spend 1963-1970s trying to find a H2 blocker - Tagemet - but “it must be stressed that...Black and his collaborators started the search with no certainty that an H2 receptors existed, let alone an H2 inhibitor....took almost a decade. (51-53)
Besides starting with biological molecules and making synthetic equivalents, you can also try varying the effects of existing drugs or molecules and narrowing their specificity. This is how they found variations on morphine for anesthesia, analgesia, and antidiarrheal drugs.
A piperidine ring is found in haloperidol, fentanyl, Remivox, and loperamide - its funny fentanyl is mostly considered a “potent anaesthtic” (54) - but with variations of different carbon rings, functional groups like hydroxyl, methl,
Question: how much does structural optimization typically improve drug effects? Is it orders of magnitude? In antibodies I think its often a few orders of magnitude improvement - in organic chem, how much is it?
“Before computers were readily available...Dr. Janssen created an analogy computing system for recording every bit of information, chemical and biological, that was gathered about his compounds.” (58)
Chapter 5 Changing the Face of Psychiatry
Pre-1950’s basically no drugs were available for schizophrenia - then reserpine, then Thorazine, Haldol
Recognition of de-institutionalization and its downsides: “the new nati psychotic drugs were responsible for an economic and social revolution....medicines made it possible for many mentall yill people to end their antisocial behavior, to behave normally in family life, and to hold jobs...methods of caring...came to be questioned...release of large numbers of psychotic patients...this was often not the case..many psychotic individuals have become part of the large population of the urban homeless” (62)
Animal models for psychiatry (!): seminal paper - “could produce catalepsy in rats...protect rats from normally lethal injections of....norepinephrine...inhibit altogether certain types of learned and condition reflexes...prevent dogs which have received...apomorphine...from vomiting.” (63)
Q: what gems were recreational or nootropic use are buried in pharmaceutical company archives? Not selective enough for pharmaceutical use or good animal model for cognition
“Fluorine and chlorine...share the common property of impeding a compound’s rapid metabolic breakdown in the body”
Haldol trials: “both recalled the amazing transformation of the psychiatric ward...usual disorderly, noisy ward was transformed through the calming effects of Haldol...some simply could not believe that such a radical transformation of their psychotic patients could be obtained merely by administering a drug...” (69)
Obvious but important research spillovers to basic science with radioactively-labeled derivatives of Haldol
Pipamperone: “improves sleep...antiautistic, disinhibiting, and resocializing”
Ritanserin: “extraordinary effects on human sleep...increasing the duration of slow-wave sleep” (80)
In the Conquest of Pain Chapter 6
Already interest in ways to reduce abuse potential of opiates (!)
Chapter 7 Pioneers Against Parasitic Disease
Dr. Robert marsbroom was a Belgian scientist who had spent many years in the Belgian Congo (pre-Independence) and comes to Jannsen after its independence; gets put to work on anti-parasitic medications. Dr. Marsbroom eventually bring onboard a number of top parasite specialists who previously worked in those colonies.
“Guided by his intuition, Dr. Janssen was convinced that the core...would be heterocyclic...it looked as if we were climbing trees to seek fish....after testing 2,721 compounds without any luck....R 6438 showed the desired activity in chickens. ” (100) but it only works in chickens because it was probably a prodrug...that takes a long time to sort out, then there’s an isomer issue, then finally levamisole is the result.
Some unexpected good side effects from levamisole: “apparent cures of herpes-like viral infections in ruminants and monkeys..calves and pigs...suddenly regained normal weight...tended to strengthen the immune systems...some patients whose cancers went into remission.” colon cancer adjuvant treatment
Chapter 8 Waging War Against Fungal Disease
(111) mentions of antibiotic overuse, patients on chemotherapy getting fungal infections,
Chapter 9
One of the original space drugs was diphenoxylate: “Dr. Charles Berry...medical chief of the US astronaut program...assist in avoiding inflight defecation when necessary.” (130)
Chapter 10 New Hope for Digestive Disorders
After 20 years of only a single GI drug, Janssen pushes for more GI drugs. Dr. Reyntjens looks into trying to find anti-nausea drugs that don’t have CNS effects.
Chemoreceptor trigger zone is not protected by blood brain barrier
Domperidone was developed but weirdly not really available in the US (?); Cisapride was too but is a little risky because of cardiac side-effects.
Chapter 11 Don’t Surrender to Allergies
“”...some Signs that flunarizine may improve the ability of a patient suffering from cerebrovascular diseases to think logically. As a result, flunarizine is used widely to improve mental functioning in the elderly.” (149)
Chapter 12 The Crusade for Animal and Plant Health
“Sabeluzole...cognition enhancer that increases the blood flow to organs and tissues. Impaired memory in the elderly is improved after only a single dose. ” (172)
“The hallmark of scientific research today...is the increasing rate and pace of change...51 years between 1830 and 1881, before...Faraday’s findings...until the first practical electrical generator...40 years before...E=Mc2...until the first atomic bomb...20 years...DNA...1971 transplanted genes from one organism to another...1957, Leo Isocki...electrons can tunnel...six years later...semiconductor diodes...Dr. Frank Press, President of the National Academy of Sciences, suggests that were are in the Golden Age of Science.” (175)
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