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defined for drugdiscoveryresearch Medicinal converse with biochemistsandbiolo- excellent organic chemists,ableto new drugtherapies.Theyhave tobe phase ofresearchingfor potential logical evaluationinthe discovery of novelorganiccompounds forbio- cerned withthedesignand synthesis medicinal chemistsaremainly con- the pharmaceuticalindustrywhere outside ofacademia.Thisissurelyin ment ofpractisingmedicinalchemists concentrate onthemajoremploy- pose ofthisarticle,however, isto ties ofmedicinalchemists.Thepur- aims tocoverthemanyvariedactivi- Applied (IUPAC) in1998, International UnionofPureand Medicinal ChemistrySectionofthe structure-activity relationship.” cular levelandtheconstructionof of theirmodeactionat their metabolism,theinterpretation ly activecompounds,thestudyof cation andpreparationofbiological- invention, discovery, design,identifi- sciences. Itisconcernedwiththe logical, medicalandpharmaceutical pline, alsoinvolvingaspectsofbio- Medicinal chemistryhasbeen The abovedefinitionfromthe 1 as: “achemistry-baseddisci- Educating Chemists the mole- Educating Chemists Department ofChemistry, ChristopherIngoldLaboratories, university setting. as formaleducationandtraining ina arises astowhatshouldbe provided excellent .The question do this.Obviouslytoo,they mustbe may havetoworkveryhard tolearn how tocommunicatewhereas others ple, somewillhardlyneedtobetold ter. Intermsofthelatter, forexam- ence, andthechemist’s owncharac- “on thejob”oracquiredbyexperi- versity, whathassincebeenlearned during theformaleducationinuni- sents amixtureofwhatwasimparted grounds. tists withdifferent trainingandback- ciently inateamcomposedofscien- municate effectively andworkeffi- drug developmentprocess,tocom- ducts; theyoughttounderstandthe to assistthescaleupoftheirpro- the needsofchemicaldevelopment inventions; theyshouldappreciate patents inordertoprotecttheir conversant withtherequirementsfor however. Medicinalchemistsmustbe represent thelimitoftheirfunctions, their requisiteabilities.Itdoesnot This probablyrepresentsthecoreof and propertiestobiologicalactivities. lable forrelatingchemicalstructure gists, andabletousethetoolsavai- for Medicinal for Medicinal EFMC -Yearbook This compositeofabilitiesrepre- Chemistr Chemistr University CollegeLondon,U.K. 2005 -2006 [email protected] C. RobinGanellin y y 21

Educating Chemists for Medicinal Chemistry The views It is surprising to find that such of pharmaceutical companies little value is attached to chemists having received some formal educa- Some years ago, the IUPAC tion in a biological topic. It seems Medicinal Chemistry Section (now part logical to employ such chemists since of Division VII, Chemistry and Human it should help them to be effective as health) canvassed the views of indus- medicinal chemists form the outset, try for their preference in hiring the instead of having to spend quite a new employees who will become their few years acquiring the additional medicinal chemists. A questionnaire understanding necessary to enable was sent out in 1996 and 1997 to them to be effectively involved in leading medicinal chemists and as well as in drug syn- research directors in the major inter- thesis. national pharmaceutical companies engaged in research and develop- The foregoing certainly accords ment. The responses were very similar with my personal experience. I and over 90% of the replies indicated trained as an organic and a preference for well trained synthetic entered the pharmaceutical industry organic chemists rather than with no knowledge of medicinal medicinal chemists. The results were chemistry or . It took reported in a series of publications me many years to learn about these relating to different countries2-4. disciplines even though I had studied

Educating Chemists for Medicinal Chemistry biology at school and for one year at The very strongly expressed opi- university as part of my undergradua- nion was that the most important edu- te course. The knowledge of some cational background required of the biology at least made me receptive to new chemists was excellent training the subsequent research discussions in synthetic . with pharmacologists, but I had to Preferably they should possess a PhD undertake a considerable amount of and postdoctoral experience from private study to learn what was laboratories of well known synthetic needed for research. organic chemists. Little interest was expressed for having chemists with A bachelor degree in medicinal formal academic training in medicinal chemistry – a proposition chemistry, or for chemists trained in but also having The above observations are rele- knowledge of biological subjects. The vant to a discussion I once had when I industrial view was that most of the was employed as a medicinal chemist medicinal chemistry aspects, other at SmithKline & French Laboratories than organic synthesis, could be (SK&F) with James Black (later Sir learned on the job or through short James Black, Nobel laureate for courses during employment. In con- or Physiology) seeking to trast, synthesis cannot be learned define histamine H2 receptors and to effectively in a practical sense through design a suitable antagonist as a useful short courses during employment drug (the work which led to the anti- although, of course, short courses are ulcer drug, cimetidine). During this a valuable way of extending know- particular conversation he was very ledge and, particularly of keeping critical of some of the chemists with abreast of recent developments. whom he had previously collaborated.

22 EFMC - Yearbook 2005 - 2006 To him, they were hidebound in Degrees in medicinal chemistry their thinking and also too ready to treat biological results as if they were The medicinal chemistry degree at precise numbers. He felt that they did UCL has endured and, over thirty years not appreciate the problem of bio- later, it still continues as a three-year logical variation and the need to B.Sc. or four-year M.Sci. (Master of understand the statistical nature of Science). The number of students bioassays. For him, the chemists varies each year but this degree course wanted to treat values from bioassay has provided 20-30% of the annual in the manner in which they consi- undergraduate entrants to the dered melting points, that is as inva- Chemistry Department. The students riant numbers. Unfortunately he felt take the same core lectures for chemis- unable to change this situation by try as do the chemists except for the dialogue with the chemists because, more advanced . as he saw it, they were no longer fle- Thus, they are given the same physical xible in their thinking. Therefore, he chemistry and organic chemistry; saw that a possible solution would be indeed they take the courses together. to get at the chemists in their early training, during the period in which Table 1. they were undergoing mental The non-chemical subjects studied by students imprinting. His solution was to have taking the medicinal chemistry degree in chemists study medicinal chemistry at University College London

university for their first degree. Educating Chemists for Medicinal Chemistry Year 1: Mammalian physiology; Cellular and . James Black left SK&F in 1973 to take the Chair of Pharmacology at Year 2: Statistics; General and Systematic University College London (UCL), as Pharmacology; Topics in . Head of Department, from which Professor Heinz Schild had just Year 3: Principles of Drug Design; Molecular Pharmacology; Receptor Mechanisms. retired. Whilst at UCL, he tried out Optional subject. his idea of training medicinal chemists on the Chemistry Department. He found that In addition to the chemistry to- Professor Charles Vernon, a biologi- pics, the medicinal chemists take the cal chemist, was receptive to this subjects outlined in Table 1 for the proposal and between them they first three years, which are taught by initiated a B.Sc. in medicinal chemis- the corresponding departments. try. It was an opportune time to They do this at the expense of being start a new degree in chemistry able to select other optional topics because the number of students but this is acceptable because they applying to study “pure” chemistry have opted to take a medicinal was falling and medicinal chemistry chemistry degree course. In the sounded attractive to some students fourth year, the students undertake leaving school who wished to com- a research project, which involves bine their chemistry with an interest 50% of their course, and can choose in a medicine-related subject. James to also study four optional subjects. Black was only at UCL for four years The latter can be selected from, for but, like all great men, he left his example: natural products chemistry, mark on the place. biological chemistry, advanced spec-

EFMC - Yearbook 2005 - 2006 23 troscopy, more-advanced organic In the third year of the medicinal synthesis, chemical computation, or chemistry degree course, the lectures a specialist biological topic. The on the principles of drug design are organic chemistry content of this particularly relevant to a future medi- course is very high since, in the cinal chemist; the stated objectives of second and third years, 25% of the these lectures are: “to understand how teaching time involves organic syn- to relate chemical structure to biologi- thesis and in the fourth year, it is cal activity and how to conduct a struc- possible to again spend 25% of the ture-activity analysis”, and “to appreci- time on organic lecture courses, and ate the various approaches to drug dis- 50% of the time on a synthetic covery and be able to exemplify organic research project. them”. The structure of this lecture course is given in Table 2. In the fourth year, approximately six case histories of Table 2. drug discovery are also presented The third year course of 30 lectures (at 45 (generally by one of the respective minutes each) on “the principles of drug design” inventors) by industrial lecturers. for medicinal chemistry students at University College London To enhance the standing of the One lecture on: medicinal chemistry degree the Introduction to . Provost at UCL at that time (Sir James Lighthill) agreed to make a Professorial Ten lectures on:

Educating Chemists for Medicinal Chemistry appointment at the research level. I Structure-Activity Relationships: Hammett equation, QSAR, the Hansch equation, found myself being invited for discus- bioisosterism, the Topliss tree, prodrugs, steric sions. Negotiations followed and I interactions, pKa's and structure-activity analysis. accepted to become the SmithKline and French Professor of Medicinal Six lectures on: Chemistry in 1986. Another lecturer inhibitors: was also appointed who was very Basis of enzyme inhibition. Transition state ana- active in research and this really did logues. Irreversible, active-site directed and suicide inhibitors. Pyridoxal phosphate dependent ensure that the Chemistry Department : inhibitors of aminoacid decarboxylases, had a pronounced research presence in transaminases, and monoamine oxidase. medicinal chemistry.

Five lectures on: There are now at least fifteen other Anti-bacterial and anti-fungal chemotherapy: Bacterial infections, an historical view. Sulfa drugs. University Chemistry departments in Penicillin, discovery and . the U.K. which offer degrees in medici- Semi-synthetic penicillins. Other , nal chemistry or a closely related sub- anti-bacterials. The development of resistance. ject such as “Chemistry for Drug Fungal infections and treatments. Fluconazole. Discovery”, “Biological Chemistry”, or Eight lectures on: “Pharmaceutical Chemistry”. Another Anti-viral and anti-cancer chemotherapy: pioneering Chemistry Department was Viral replication. DNA-containing viruses: herpes the one at Loughborough where simplex virus. Intervention in the viral life-cycle: Professor Ken W. Bentley, initiated a penetration, antimetabolites, replication, and trans- medicinal chemistry degree course in cription inhibitors. Retroviruses: HIV. Life cycle, anti- the 1970’s which is still active; Bentley HIV drugs. Biology of cancer: tumour suppressor and promoter genes. DNA as a target: alkylating, had left Reckitt and Colman laborato- intercalating, and strand-cleavage agents, minor ries after inventing the very potent ori- groove binders. Antimetabolites, natural products. pavine class of morphine-like anal-

24 EFMC - Yearbook 2005 - 2006 gesics (Diels-Alder adducts derived cal synthesis and presumably that is the from thebaine) one of which is reason why they seek for the best syn- buprenorphine. thetic organic chemists. When it comes to the decision taking of which types Employment for medicinal of structures to synthesise, or what chemists in big pharma properties to be aiming for, however, the companies probably only need a If bright students with first class few medicinal chemists to interface degrees from these courses continue with the biochemists and biologists, their studies by completing PhD’s with and to take the main decisions about well known outstanding and highly which chemical structures to pursue. regarded synthetic organic chemists then they will surely be able to win This has become even more evident employment as research medicinal with the further separation of chemist chemists in the pharmaceutical indus- functions into library synthesis for lead try, and they will have conformed to Sir generation, lead development, optimi- James Black’s ideal. sation of drug candidate structures with respect to drug disposition and Of course, medicinal chemistry unwanted toxic or side effects, and graduates can pursue their PhD studies scale-up synthesis for development. in other chemical specialities such as There are also many other chemists computing, or physical-organic chemis- involved in various functions, for

try topics, or in , or drug example, in the measurement of Educating Chemists for Medicinal Chemistry metabolism etc. The nature of the chemical properties relevant to drug topic will generally determine the area discovery and development, or as of research in which they may seek computational chemists for employment. conformational analysis and structure- activity analysis, or in information Many medicinal chemistry gradua- technology, and subs- tes may choose not to continue in uni- tance analysis and so on. With so many versity for a research qualification but interconnecting specialities it is, after go into teaching or directly into indus- all, not surprising that there is only a try. They will most probably not work minor proportion of medicinal as medicinal chemists in drug discov- chemists required to provide the ery. There are many other suitable leadership in drug design. types of positions for medicinal chemists available in the industry, for Employment for medicinal example: as Clinical Research Assistants chemists in small pharma or Clinical Trials Coordinators, or in Regulatory Affairs, in Information There is a considerable contrast Retrieval or Patents, in Process between big pharma as described Development, as Sales Representatives above and the small research compa- or in Marketing etc. nies or biotech companies which do not possess large teams of chemists. In The highly sophisticated organisa- the small companies, individual scien- tion of discovery research in big phar- tists may have to fulfil many functions, ma depends upon the integration of that is they have to act as generalists many different specialities. Their rather than as specialists. Under these greatest need for chemists is in chemi- circumstances the medicinal chemistry

EFMC - Yearbook 2005 - 2006 25 graduate is probably extremely well mounted. My interest in medicinal prepared for the interaction that must chemistry as a scientific discipline also occur with the various biologically led me to become involved with the based activities. Royal Society of Chemistry (RSC) Summer School when I was at SK&F . Small biotech companies, of which My colleague, Dr AM Roe, was there are many, often have severe limi- Chairman of the RSC Education tations in the number of scientists that Committee which advised the RSC on they can afford to employ and they the various courses mounted for post require people who are able to con- graduate chemists on specialist topics. tribute in a multifunctional manner. These were usually residential and They are certainly not able to train each lasted for approximately one their own medicinal chemists; there- week. One such course had started in fore they seek personnel who have 1979 as a week’s summer school in already developed medicinal chemistry medicinal chemistry but it had not skills and are capable of immediately attracted enough chemists from the interacting productively with scientists pharmaceutical industry, possibly from other disciplines, especially from because it appeared to be overly the biological sciences. dependent on techniques of structure determination and chemical analysis. One way of getting trained medici- Anthony Roe invited me to think up a nal chemists is to attract experienced suitable syllabus.

Educating Chemists for Medicinal Chemistry scientists away from the big research based companies. Sometimes they Our aim was to provide a rapid become available as a consequence of and concentrated conversion course a merger taking place between big for recently hired postdoctoral companies to form even larger compa- research chemists in the pharmaceu- nies but with fewer total staff, e.g. as tical industry; in the main these were occurred during a decade in which organic chemists who needed to GlaxoSmithKline was formed from the know what was required to become four large research companies, Glaxo, a practising medicinal chemist. My Wellcome, SmithKline and French, and past experience had shown me that Beecham Products. The supply of such such courses usually dealt with dis- trained professional medicinal eases and their test models but I chemists is clearly limited and, decided to avoid this approach. I felt presumably, small companies cannot that one should aim to introduce, as just wait until an appropriate merger well as possible, the principles of the takes place between big companies. subject. It seemed to me that the Therefore in this sector there should basic discipline for medicinal be many opportunities for employ- chemists was to understand struc- ment available to recently qualified ture-activity analysis and the inter- medicinal chemists. face with the other disciplines involved in drug discovery. Thus the Short courses core lectures would be on physico- in medicinal chemistry chemical properties (octanol-water partition, pKa and hydrogen-bond- To assist organic chemists to appre- ing, conformational analysis), multi- ciate what is required of a medicinal parameter correlation analysis and chemist, short courses have been computation, biological targets and

26 EFMC - Yearbook 2005 - 2006 Table 3. Syllabus for a one-week school as an introduction to medicinal chemistry. The published5 syllabus compared with the recent RSC school in Nottingham University, U.K., 4 - 8 July 2005. The lectures from the latter are asterisked.

I Introduction: * 1. Research strategy II Biological targets: * 2. Lead generation/sources for drugs * 3. Receptors and drug-receptor interactions * 4. Enzymes and design inhibitors 5. channels, membranes and transporters * 6. Second messengers III Bioassay: T 7. Screening methods and the information that they provide T 8. Determining activity: principles of pharmacological , biological variation (and the need for statistics), in vitro and in vivo methods IV Structure-activity methods: * 9. Physicochemical concepts, including pKa, solvent partition, Hammett, H-bonding, steric parameters * 10. QSAR, parameterization and computer assisted lead optimization, statistical methods * 11. Molecular modeling, energy calculations and molecular graphics 12. Operational strategies in molecular modification, identification, conformational restriction, isosterism, lipophilicity control, solubilisation T 13. Development of a lead compound (a tutorial exercise) V Biodisposition and implications: * 14. , concepts, parameters and modeling * 15. 16. Prodrugs * 17. Molecular and avoidance of toxic intermediates VI Case studies: * 3 or 4 case studies of drug discovery VII Special topics selected from the

following possibilities: Bio-organic chemistry Educating Chemists for Medicinal Chemistry Chirality in drug action Clinical pharmacology * Drug delivery Ethical considerations * † Historical: approaches to discovering drugs * Molecular biology: role in drug discovery Nucleotides * Patents Peptidomimetics Regulatory procedures * † Structure-guided drug design

T = Tutorial † new, not in ref.5 bioassay, receptors and enzymes, ion type was mounted in 1981 and the channels and transporters, drug dis- result was a resounding success. It position (dmpk) and the drug has since been repeated in alternate development process. We would also years, always oversubscribed and include several case histories of drug with a healthy participation of dele- discovery (something which I had gates from continental Europe. It previously encountered in a Society has received further accolade by pro- for Drug Research Symposium). viding the model for the annual Lecturers were mainly industrial, and course put on in the USA since 1987 the number of participants was limi- at Drew University, Madison, N.J. ted to around 100 to foster a more intimate and informal atmosphere. An early example5 for a week- long syllabus is indicated in Table 3. The first “summer school” of this This is compared with the most

EFMC - Yearbook 2005 - 2006 27 recent RSC summer school held on usually open to non-employees to Nottingham University campus, U.K. attend. on 4-8 July 2005. Some special topics have been included (indicated by *) Schools of Pharmacy in place of lectures on ion channels (N°5), operational strategies (N°12), The title of this short article and prodrugs (N°16). Three other “Educating Chemists for Medicinal lecture topics (N° 7, 8 and 13) are Chemistry” is meant to convey that it is presented as optional tutorials. The aimed at the education of real practi- drug delivery topic was on “compu- sing research oriented medicinal tational approaches to pre-formula- chemists. It has not been discussing the tion and formulation design”. Some teaching of medicinal chemistry per se. of the lecture subject matter or It is an expansion of thoughts emphasis has probably changed expressed earlier, e.g. in reference 6. somewhat but generally, the philos- Traditionally, the formal university ophy of the approach has been teaching of medicinal chemistry takes retained. place in the faculties or schools of phar- macy. There, medicinal chemistry is only Other short courses are also avai- one of a variety of subjects taught at lable in other countries, for exam- the undergraduate level where the ple: at the Leiden-Amsterdam focus is on education of future practis- Center for Drug Research in ing . Presumably the aim is

Educating Chemists for Medicinal Chemistry Noordwijkerhout in the to give pharmacists some under- Netherlands, the Swiss Course on standing of how new medicinally use- Medicinal Chemistry, Leysin, ful drugs are discovered. The combined Switzerland, at the Danish results of the responses to a question- University of Pharmaceutical naire sent to schools of pharmacy have Sciences in Copenhagen Denmark, been published.7-9 and the Italian Advanced School of Medicinal Chemistry for Ph.D. stu- Undergraduate medicinal chemis- dents and young researchers which try is usually taught by academic staff is held annually in Urbino, Italy. who are practising medicinal chemists Some of these courses tend to be working at the research level in some “extension courses” in that they aim aspect of drug design. These acade- to extend the knowledge of medici- mics are usually also involved in super- nal chemistry students or vising postgraduate students and/or researchers rather than being “con- postdoctoral researchers. The interes- version courses” aimed at non- ting question arises as to where the medicinal organic chemists. Many postgraduate students had spent their other courses exist, run commercial- undergraduate education. Did they ly or by universities, and these are graduate from a pharmacy course or a usually mounted locally and focus chemistry course? on a specialized area of medicinal chemistry or its application. Many of If students obtain both of their the big research-based pharmaceuti- qualifications (i.e. bachelors degree cal companies also run their own in- and doctorate) from a school of phar- house training courses of both types macy then the issue which arises for an i.e. conversion courses and exten- employer seeking chemists for drug sion courses. Naturally, these are not discovery is whether the prospective

28 EFMC - Yearbook 2005 - 2006 employee has had sufficient exposure would be appreciated by a prospective to chemistry and, especially, to synthe- employer. The extent of chemical train- tic organic chemistry. For the latter, ing and chemical achievement demon- there is a marked contrast in the strated by a student will provide the organic chemistry training for a PhD basis for an employer to judge degree if the student has been whether they wish to offer a job to a involved in new method development, prospective employee, presenting or synthesis of a complex target mole- themselves as a medicinal chemist. cule, in comparison with a student who has synthesized a series of struc- Summary turally similar using a repe- titive synthesis procedure. This article discusses the education of Departments of Pharmacy vary consid- medicinal chemists who will be active erably at the postgraduate level and in drug discovery research in the phar- what they teach depends very much on maceutical industry. The main theme is the specialisms of the academic teach- the combination of education in syn- ing staff. Some Departments may spe- thetic organic chemistry with other cialise in drug delivery or drug formu- subjects relevant to medicinal chemis- lation, others might be more involved try. It is anticipated that such chemists in drug safety or biochemistry. Some will be acceptable for employment in are undoubtedly distinguished in the major R&D-active pharmaceutical and new drug companies.

design and one would hope that this Educating Chemists for Medicinal Chemistry

References

1 C.G. Wermuth, C.R. Ganellin, P. Lindberg and L.A. Mitscher. Glossary of Terms used in Medicinal Chemistry. Pure & Appl. Chem. 1998, 70, 1129-1143. also in Ann. Rep. of Med. Chem. 1998, 34, Chapt. 36, pp 385-395. http:/www.chem./qmul.ac.uk/iupac/medchem

2 C.R. Ganellin and W.D. Busse. Views from Industry on the Medicinal Chemistry Curriculum: Answers to a Questionnaire. in “Trends in Receptor Research” Ed. V.Claassen, Pharmacochemistry Library, Vol.20, Elsevier, Amsterdam, 1993, pp 305-315.

3 C.R. Ganellin, L.A. Mitscher and J.G. Topliss. Educating Medicinal Chemists. Ann. Rep. Med. Chem. 1995, 30, Chapt. 33, pp 329-338.

4 W.D. Busse, C.R. Ganellin and L.A. Mitscher. Vocational Training for Medicinal Chemists: Views from Industry. Eur.J.Med.Chem. 1996, 31, 747-760.

5 C.R. Ganellin. Syllabus for a Short Postgraduate Course in Medicinal Chemistry. Chem. International, 1995, 17, 212-214.

6 C.R. Ganellin. Two Routes to Becoming a Medicinal Chemist. Chem. International, 2001, 23, 43-45.

7 C.R. Ganellin, L.A. Mitscher, B. Clement, T.H. Kobayashi, E. Kyburz, A. Marcincal, A. Monge, G. Tarzia and J. Topliss. University Education of Medicinal Chemists: Comparison of Eight Countries. Eur. J. Med. Chem. 2000, 35, 163-174.

8 C.R. Ganellin, L.A. Mitscher and J.G. Topliss. Education of Medicinal Chemists in Departments of Medicinal Chemistry (USA). Medicinal Research Reviews, 1998, 18, 121-137.

9 T.-H. Kobayashi and C.R. Ganellin. Medicinal Chemistry Graduate School Curriculum and Contribution to Pharmaceutical Industry in Japan. Med. Chem. News, 1998, 8 (4), 21-28

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