Successful Drug Discovery

Over the past one hundred years IUPAC has broadened its activities beyond a focus on the creation of a common language for chemistry. One of its core values is to encourage and support collaboration and communication among all its stakeholders and as a result IUPAC has developed a diverse portfolio of essential tools for the global application and communication of chemical knowledge. This collaboration is accomplished through the IUPAC Project system and this IUPAC Story is one of many examples of how successful and effective the Project system has become.

This IUPAC Story is about the book series, Successful Drug Discoveries, that resulted from IUPAC Project 2013-016-1-700. It is in the words of the Project chair, Dr. János Fischer (JF), currently an Associate Member of IUPAC Division VII, Chemistry and human Health, as noted in an interview by Ms. Zsuzanna Ferencz (ZF), Head of Library and Information Services at Gedeon Richter Plc where Dr. Fischer is research advisor. Read on and see how IUPAC supports an active global research network in their development of essential information resources. In Dr. Fischer’s own words “… my membership in IUPAC, and the personal contacts that came with it, played a big role in compiling all the volumes.” Thanks are due to Krisztina Rozsnyai for the English translation.

Any chemist or group of chemists from around the globe can submit a project proposal – they do not have to be part of an IUPAC Body. Proposals are reviewed in details and, if approved, funding is provided to the Project task group. Project deliverables can include traditional standardization of nomenclature and terminology, glossaries in specific fields, data standards, etc. The system facilitates a speedy resolution of problems while engaging the active participation of chemists worldwide who volunteer their time and expertise to address the problems of greatest importance that fall within IUPAC’s scope; i.e., they address at least one of the goals listed in the IUPAC Strategic Plan and satisfy a least one of the following criteria: (a) the proposals should be related to the needs of chemists around the world, not just those in a specific country or region; (b) they should be related to the role of chemistry for the needs of mankind; or (c) they should be best tackled by an international team. For more information on the IUPAC Project System, see <iupac.org/what-we-do/projects/>.

(JF) Three factors gave me the impetus for coming out with the series Successful Drug Discovery (SDD). One was the three-volume Analogue-based Drug Discovery (ABDD), published by Wiley in 2006, 2010 and 2013, which was successful and through which I established a good working relationship with the publisher, Wiley-VCH. They suggested starting a new series entitled Successful Drug Discovery that would cover all drug discoveries, not only the analogue-based ones.

A second incentive came from the IUPAC Subcommittee on Drug Discovery and Development that Robin Ganellin chaired from 2001 to 2011. He supported, and actively participated in, demonstrating that ongoing optimization of drugs within a drug class could be a useful and beneficial activity.  By professionally collecting drug discovery stories we sought to refute the pejoratively used expression “me too” that considered neither the practical nor the theoretical significance of the constant development going on in most drug classes, which often leads to new and better drugs.

Finally, the third incentive came from the fact that the project structure of IUPAC itself supports any project proposal deemed to be useful for the professional public. The projects are usually given two years to complete, affording modest financing that covers travel costs for project meetings.

(JF) I edited the first two volumes of Analogue-based Drug Discovery (ABDD) with the famous British drug researcher, Robin Ganellin, and for the third volume David Rotella from the U.S. joined the editorial board. Volume 1 of the ABDD comprises three parts and twenty-three chapters. (DOI: 10.1002/3527608001, Wiley Online Library) The first part deals with general aspects of drug discovery. The second, largest part, examines the optimization of drugs in nineteen drug classes. The third part presents in ninety pages of tables an overview of components of the most important drug classes together with their structural formulas, International Nonproprietary Names, molecular weight, and two significant dates, the year of the basic patent and when they were launched to the market.

My colleagues at Richter played an important part in these volumes.  I wrote a chapter on ACE inhibitors and angiotensin receptor blockers.  Béla Kiss and István Bitter wrote the chapter on clozapine analogues. Zoltán Tuba reviewed the corticosteroids. I have my colleague Erika Alapi to thank for compiling the tables of the analogues.   My membership in IUPAC also gave me access to a plethora of renowned drug discovery scientists whom I prevailed upon to contribute.  In selecting the authors, the primary consideration was their competence. We paid great attention to get researchers on board who had played a key role in developing the drug that was the subject of the chapter.   For example:

• Camille Wermuth, a professor at Strasbourg, wrote the chapter on analogues as a means of discovering new drugs.
• Robin Ganellin, considered to be the father of cimetidine, reviewed the H2-receptor antagonists. He was our guest twice at Richter. I have learned a lot from Robin. He has a wonderful writing style and his clear and logical sentences and presentations are exemplary.
• Per Lindberg, a renowned researcher at AstraZeneca, wrote the chapter in the first volume on proton-pump inhibitors, which also contains a case history on esomeprazole.
• Joerg Senn-Bilfinger from Konstanz played a key role in the discovery of pantoprazole, on which he wrote the case history.
• Giovanni Gaviraghi from Siena wrote the case history on lacidipine as an important calcium channel blocker-based blood pressure lowering agent. Giovanni was a key discoverer of lacidipine.
• Zeev Tashma from Israel described the discovery of rivastigmine in his chapter on “stigmines”. Eli Breuer, a researcher from Jerusalem, helped me to contact Zeev. Eli Breuer is a prominent phosphorous chemist who was born in Pápa (Hungary). He is eighty-four years of age but continues to do research at the university and speaks Hungarian without any accent.
• Rudolf Wiechert summarized the history of drospirenone. Professor Wiechert was research director at Schering. We were good friends and he came to give a lecture at Richter.

The work of thirty to forty authors needs to be coordinated for each volume. Of course I was in mail contact with the authors as well as the reviewers of each chapter, deciding on the latter being part of the editor’s job. The book introduced all contributors of the chapters with their photos and CVs. The series lays great emphasis on the significance of the personality.

In brief, my membership in IUPAC and the personal contacts that came with it played a big role in compiling all the volumes.

(JF) To answer this question let me come to the new series that started in 2015, titled Successful Drug Discovery (SDD). Three volumes have appeared so far, the first in 2015 (DOI: 10.1002/9783527678433, Wiley Online Library), the second one in 2016 (DOI: 10.1002/9783527800315), and the third one in 2018 (DOI: 10.1002/9783527808694). Editing a work of this kind is fundamentally different from editing a journal. You cannot expect articles to come in automatically. We have to select each subject and author, which poses difficulties. We decided to continue the structure used in the three volumes of Analogue-based Drug Discovery. The first parts of the books deal with general aspects of drug discovery and the second with the optimization of drugs within a drug class. The third part, which is probably the most important, describes case histories of drug discoveries, where we selected the author from among the researchers who had played a key role in the discovery of the drug in question.

Together with David Rotella, one of my co-editors in the ABDD series, I wrote the first chapter of the first volume about the important role of serendipity in a drug discovery. Serendipity is difficult to express with other words, “lucky coincidence” would probably best capture its meaning. We chose this subject because it is worth reminding drug researchers that serendipity seems to play some role in practically all aspects of drug discovery. We examined five important drug discoveries to illustrate our point.

To follow this general chapter, we looked for a drug class story and our choice fell on insulin and insulin analogues. Its author, John Beals, was a leading researcher at Lilly. It was a good choice, since he wrote an excellent chapter for the first volume of Successful Drug Discovery. He highlighted the products of three large companies that dominate the insulin analogues market, American Eli Lilly, French Sanofi, and Danish NovoNordisk. I was also happy about this chapter because insulin and insulin analogues, as polypeptides consisting of fifty-one amino acids, constitute a transition from small-molecule drugs to the large molecule biologics that are gaining ever more significance nowadays.

The first volume of SDD covered eight drug discovery case histories. In each product, the authors had contributed to discovering the drug. Three chapters were written by Japanese researchers. This was accomplished through my connection with one of the members of the advisory board, Kazumi Kondo, a researcher at Otsuka.  One chapter subject was avanafil, which is an enzyme inhibitor that acts faster than sildenafil.  The second chapter dealt with a new antiepileptic drug called perampanel, described by a researcher from Eisai. The third was a new AIDS drug called elvitegravir, whose mechanism is based on the inhibition of the integrase enzyme of the HIV-1 virus.

The book described another antiviral drug discovery described by researchers from the American company, Vertex. This discovery of telaprevir led to the successful introduction of a hepatitis C drug, whose significance quickly dropped following the discovery of sofosbuvir. For this chapter I approached a researcher at the Gordon Research Conference and he agreed to write the chapter.

Another quickly developing field of pharmaceutical research field is type 2 diabetes mellitus. The anti-diabetic agent dapagliflozin was a pioneering discovery. Again, I met the author of this chapter, William Washburn, at a research conference and was able to get him on board to write the chapter. The drug inhibits the protein SGLT2, which raises the blood sugar level but allows more glucose to be eliminated with the urine. Another antidiabetic drug, linagiptin, is a long-acting DPP-4 enzyme inhibitor developed by Boehringer Ingelheim. Matthias Eckhardt accepted the invitation, which was supported by research director, Gerd Schnorrenberg. I have known him for a long time, reaching back to the mid-1980s, when I was completing my research with a Humboldt scholarship in Bonn. I met Gerd back then as he was getting his doctorate at the same institute.

The other three subjects concerned anticancer research, which nowadays is prevalent in international drug research. The first one was pemetrexed, a beautiful example for the successful collaboration between university and industry. David Rotella knew Edward Taylor, a researcher at Princeton University. Taylor was interested in pterin chemistry and was doing research on folic acid antimetabolites. He was able to discover a valuable lead compound that was taken on by Lilly, and the collaboration produced an anticancer drug called pemetrexed, which is applied primarily in small-cell lung cancer cases. Another anticancer drug discussed in the volume is called trastuzumab emtansine, which was described by the Swiss-American Genentech team. The monoclonal antibody drug-conjugate is used in breast cancer therapy. Again, it was a conference that brought me into contact with the chapter’s author Jagath Reddy Jumutula, an American researcher.

Most of the drugs presented in volume 1 of SDD are so-called blockbuster drugs, which means they produced over a billion US dollars in sales per year at some point in their lifetime. One consideration for selecting these subjects was timeliness. The American and/or European authorities had already approved them but these approvals were fairly recent, occurring within four or five years before the writing of the chapters. The only exception was pemetrexed, which had been approved to treat lung cancer in 2004. The review of this highly significant and successful drug was a valuable part of the book because of its high impact on the field of cancer drug discovery.

After the success of the 2015 volume we started in 2016 at the request of the publisher to put together the second volume of Successful Drug Discovery. David Rotella, professor at Montclair University, was not able to continue this work, but he recommended Wayne E. Childers from Temple University as co-editor. Wayne Childers accepted and did a wonderful job in bringing the second volume to fruition.

We had intended to follow the earlier structure of the first volume but it was challenging to identify good themes for general aspects or drug class studies in a timely manner. However, we were able to collect several excellent case histories, so the second volume represents a kind of supplement to the first volume, with eleven case histories. All of them dealt with medicinal chemistry subjects. I also wanted to ease my editing work by inviting section editors.  The HDAC inhibitor anticancer section turned out especially well.  The section editor was the British professor A. Ganesan, who was able to compile case histories on all five marketed drugs within this class.

Another section contained a single drug, abiraterone, which works by inhibiting the CYP17 enzyme and is used to treat prostate cancer. The section editor, Juan-Miguel Jimenez, helped me with the reviewing. The difficulty lay in obtaining the chapter. The British researcher Garry Potter played a key role in its discovery and he agreed to write the chapter but he suffered from health issues and was not able to get beyond the synopsis. We resolved the issue by having steroid researchers working at the American company Sage write the chapter. My colleague Sándor Mahó helped to review the manuscript and he played an important role in getting the chapter into press.

Alarming reports have been emerging for some time about resistant pathogen bacterial strains coupled with a radical drop in antibiotic research at pharmaceutical companies. In the second volume, researchers from the Japanese firm Otsuka describe the discovery of delamanid, a new drug for tuberculosis, which has become resistant to a number of other drugs. This is significant because there are over ten millions new TB cases worldwide. The drug acts by inhibiting the biosynthesis of lipid-like mycolic acid. The Japanese adviser Kazumi Kondo helped to contact the authors.

The discovery of sofosbuvir, which actually cures patients with Hepatitis C, was a huge success in the history of pharmaceutical research. A small research firm in the U.S. discovered how an active nucleoside base, which due to its bad pharmacokinetics could not be developed into a drug.  It could be made to reach the liver, however, with the help of a prodrug approach, where it destroys the virus. The discovery comes from Michael Sofia, an American researcher, who was awarded the IUPAC-Richter Prize in Manchester in 2016. We were honoured that he came to the Research Forum of Richter Plc in October 2017 where he gave a plenary lecture to the researchers. Sofosbuvir has been on the market since 2013 and has completely cured over a million patients of the virus which, without treatment, could lead to liver cirrhosis, cancer and ultimately death.

As an example of research within the central nervous system, the Danish researcher, Benny Bang-Andersen, from Lundbeck, described the discovery of the antidepressant vortioxetine. The drug works by increasing the serotonin level in the brain and is highly-effective in treating depression and the cognitive deficits that occur as a result of depression.

Takeda researchers wrote a case history about a new drug called vonoprazan. It inhibits gastric acid secretion and has a considerably longer effect than proton pump inhibitors, with a mechanism of action that differs from any earlier gastric acid reduction agents.

Last, but not least, the volume contained a case history on nintedanib, a new kinase inhibitor drug discovered by researchers at Boehringer Ingelheim, which is primarily used to treat pulmonary fibrosis and is also effective against certain cancers.

In summary, Successful Drug Discovery volume 2 (DOI: 10.1002/9783527800315, Wiley Online Library) covers eleven case histories in six different therapeutic areas.  It came on sale as a book and e-book in December 2016. The cost of the latter is slightly lower.

The third volume was recently completed and appeared in April 2018 (DOI: 10.1002/9783527808694). It consists of fifteen chapters. We reverted to the structure of the first volume, which involves three sections. In part 1 (General Aspects), Gerd Schnorrenberg gives an excellent overview on small-molecule drugs and trends in biologics. Another chapter recapitulates patent issues and is sure to make helpful reading for all drug researchers whether they deal with small or large molecules. The second part of this book deals with drug classes and the third one describes eleven case histories authored by the discoverers.  For brevity, I will mention only one case history, in which the Italian professor Pellicciari describes the discovery of obeticholic acid. The drug developed by the researchers from Perugia has been approved for the treatment of primary biliary cholangitis by the FDA in the U.S.

(JF) I finished my work at Richter as head of a research laboratory in 2006 and in the ten years since then six books have been published, three of them under the title Analogue-based Drug Discovery and three within the new series called Successful Drug Discovery, which comes to an average of one volume every two years. With the new series we were able to shorten the time from start to finish to a year. The first volume came out in 2015, the second one in 2016 and the third appeared in April of 2018 due to some unforeseen and unavoidable delays for the publisher.

(JF) I was at a conference in Switzerland, in Bürgenstock, in 2004 or 2005. As a guest of Andrea Vasella, a professor in Zurich, I met the editor in chief of Helvetica Chimica Acta, a Turkish gentleman named Kisakürek. I mentioned the planned IUPAC project and book to him. At this conference, there was a colleague from Germany who brought to my attention the German unit of the U.S. publisher Wiley and I got into contact with its director, Eva Wille. I remember liking the Wiley offer better, although I don’t recall the exact details after all these years. I initially agreed with the publisher that I would decline my editor’s fee for the IUPAC’s benefit. I considered this appropriate since IUPAC supports the book project and this way, I am able to reimburse the costs of the project meetings.

(JF) The book is a product and the most important consideration about its reception from the publisher’s standpoint is if they are able to sell it. The fact that we made a contract for the seventh volume with the publisher speaks for itself. I received statistics on the e-book version readership. The publisher registered how many users bought chapters on specific subjects. There are already detailed figures on the first volume and they indicate that the interest on all chapters is about equal, including the one on biologics. This usage analysis supported our choice of topics. I am also gratified to say that the journals ChemMedChem and Chemistry International both published good reviews on the book.

(JF) With the first two volumes I had American co-editors, David Rotella from Montclair University for the first one and Wayne Childers from Temple University for the second one. For this third volume, Dr. Childers and I are joined by Christian Klein, an expert on biologics at the Swiss company Roche. This editorial team is working now on the fourth volume of Successful Drug Discovery. (IUPAC Project 2018-001-3-700)

(JF) Each volume constitutes a new creation, with all the difficulties that come with the process. The most challenging part of the book series is to compose a correct and balanced selection of subjects and to find competent authors for them. Sometimes, I feel almost like a detective. But -and I mentioned this already- it is also difficult to treat medicinal chemistry and biologics together, given that these are two different worlds. Whether this decision was a good one is something that only time will tell. In the introduction to the most recent volume the author envisions that the two branches of drug research, drug chemistry and biologics, will come ever closer, and if that is so, it is right to treat them together in one volume as was envisioned several years ago.