Medicinal Chemistry and the Pharmacy Curriculum

REVIEWS

Medicinal Chemistry and the Pharmacy Curriculum

M.O. Faruk Khan, PhD, MPharm,a Michael J. Deimling, PhD,b and Ashok Philip, PhDc

aCollege of Pharmacy, Southwestern Oklahoma State UniversitybPhiladelphia College of Osteopathic Medicine, School of Pharmacy – Georgia CampuscUnion University School of Pharmacy

Submitted March 17, 2011; accepted May 18, 2011; published October 11, 2011.

The origins and advancements of pharmacy, medicinal chemistry, and drug discovery are interwovenin nature. Medicinal chemistry provides pharmacy students with a thorough understanding of drugmechanisms of action, structure-activity relationships (SAR), acid-base and physicochemical proper-ties, and absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles. A compre-hensive understanding of the chemical basis of drug action equips pharmacy students with the ability toanswer rationally the “why” and “how” questions related to drug action and it sets the pharmacist apartas the chemical expert among health care professionals. By imparting an exclusive knowledge base,medicinal chemistry plays a vital role in providing critical thinking and evidence-based problem-solvingskills to pharmacy students, enabling them to make optimal patient-specific therapeutic decisions. Thisreview highlights the parallel nature of the history of pharmacy and medicinal chemistry, as well as thekey elements of medicinal chemistry and drug discovery that make it an indispensable component of thepharmacy curriculum.

Keywords: curriculum, medicinal chemistry, history of pharmacy, drug discovery

INTRODUCTIONIt was not until the mid 19th century that pharmacy

emerged as a professional entity in the United States. In1869, William Proctor Jr defined pharmacy as the “art ofpreparing and dispensing medicine” which “embodies theknowledge and skill requisite to carry them out to prac-tice.”1 Thus, preparation and dispensing have been at theheart of pharmacy practice since the beginning of the pro-fession, with sound knowledge of chemical compatibility,solubility, and stability of the drugs deemed essential toeffectively accomplish the “preparation” component of theprescription.1

Over the last 4 decades, the role of a pharmacist pro-gressively shifted from being a compounder and supplierof pharmaceutical products to a service and informationprovider, and eventually to a comprehensive patient careprovider.2 In 1990,Hepler andStrandcalled for a paradigmshift to “pharmaceutical care,” a concept that is defined as“the responsible provision of drug therapy for the purposeof achieving definite outcomes that improve a patient’squality of life.”2 The Omnibus Budget Reconciliation

Act of 1990 (OBRA 1990) increased the clinical responsi-bility of pharmacists by requiring them to counsel Medic-aid patients andparticipate inprospective and retrospectivedrug utilization review programs. Responding to this chal-lenge,UScolleges and schools of pharmacymoved towardoffering the PharmD program.1

The advent of this new direction for the pharmacyprofession prompted an increase in the clinical courseworkin the pharmacy curriculum. Unfortunately, this paradigmshift also initiated a debate over the relevance ofmedicinalchemistry, a basic pharmaceutical science, in pharmacyeducation. The Accreditation Council for Pharmacy Edu-cation (ACPE) Standard No. 13 clearly states the need toprovide a thorough scientific foundation for the achieve-ment of desired professional outcomes.3 To achieve thisgoal, ACPE requires the curriculum to contain biomedicalsciences, pharmaceutical sciences, social/behavioral/administrative sciences, and clinical sciences.3 Additionalguidelines specify the medicinal chemistry requirementsunder the umbrella of pharmaceutical sciences (Table 1).

Important historic milestones and the interrelationshipbetweendrugdiscovery anddevelopment,medicinal chem-istry, and the pharmacy profession are highlighted in thetable in Appendix 1.4-16 While drug development and me-dicinal chemistry are purely scientific, the pharmacy pro-fessiondealswith the art of preparing anddispensingaswellas providing optimal pharmaceutical care with therapeutic

CorrespondingAuthor:M. O. Faruk Khan, BPharm, MPharm,PhD, Department of Pharmaceutical Sciences, College ofPharmacy, Southwestern Oklahoma State University, 100Campus Drive, Weatherford, OK 73096. Email: [email protected]; Tel: 580-774-3064; Fax: 580-774-7020.

American Journal of Pharmaceutical Education 2011; 75 (8) Article 161.

1

agents. In pharmacy, the hallmark of the new millenniumhas been the tremendous advancements made in the areaof pharmacogenomics, whereby dosages of medicationsare tailored to individual patients based on specific genomicpatterns, polymorphisms, and therapeutic responses to se-lect drugs.Thus, pharmacogenomics is a rapidlydevelopingarea that lends the application of biotechnology principlesto the efficient practice of pharmacy.

HISTORY OF MEDICINAL CHEMISTRYFrom a fertile mix of ancient folkmedicine and early

natural-product chemistry, medicinal chemistry emergedabout 150 years ago as a distinct discipline. This area ofstudy received formal recognition 78 years ago with itsinclusion in the 4-year BSPharm degree curriculum.1,6

The 19th century may be viewed as the birth period ofmodernmedicinal chemistry with the introduction of sidechain theory of drug action in 1885 by Berlin immunol-ogist Ehrlich.8 Later in 1891, he coined the term chemo-therapy and defined it as “the chemical entities exhibitingselective toxicities against particular infectious agent.”4

Themodern drug receptor theory originated from this sidechain theory,whichwas supported during the same period(mid-1890s) by Cambridge physiologist Langley who de-scribed it in his publications as “receptive substances.”The importance of receptors for understanding diversebiological processes was recognized initially by Ehrlichand Langley and then followed by Clark in the 1930s. Re-search on enzyme specificity (lock-and-key theory) byFischer in 1894 and Henry’s hypothesis on enzyme-substrate complex formation in 1903 are recognized askey advancements in the principles of drug action andmod-ern medicinal chemistry.9 Grimm’s and Erlenmeyer’s con-cepts of isosterism and bioisoterism (1929-1931) also hada tremendous impact on the understanding of structure ac-tivity relationship (SAR)of drugs anddevelopment ofmod-ern medicinal chemistry.7 Other notable advancements inunderstanding of drug action and design that were made inthe mid to late 20th century include: intervention of charge

transfer (Kosower, 1955); induced-fit theory of drug action(Koshland, 1958); concepts of drug latentiation (Harper,1959) and prodrug (Albert, 1960); application of mathe-maticalmethods tomedicinal chemistry and transformationof SARstudies into quantitative SAR (QSAR) (Hansch andothers, 1960s); and application of artificial intelligence todrug research (Chu, 1974).10

Medicinal chemistry is defined as an interdependentmature science that is a combination of applied (medi-cine) and basic (chemistry) sciences. It encompasses thediscovery, development, identification, and interpretationof the mode of action of biologically active compounds atthe molecular level. Medicinal chemistry may be viewedas the melting pot of synthetic chemistry and molecularpharmacology that emphasizes the study of SAR of drugmolecules; it therefore requires a clear understanding ofboth chemical and pharmacological principles. At an insti-tutional level in the United States, medicinal chemistry firststarted as the division of pharmaceutical chemistry (1909-1920), was modified to the division of medicinal products(1920-1948) and later got its name, the division of medic-inal chemistry, from the American Chemical Society.16

Medicinal chemistry continues to play a major role indrug research and development, taking advantage of newertechniques and increased knowledge of different branchesof related sciences. The roots of modern medicinal chem-istry, however, lie in all branches of chemistry and biology,which began its journey in the battle against diseases in therevered hands of Ehrlich who dreamed of a “magic bullet”to combat all infectious diseases. Out of 114 US collegesand schools of pharmacy, 20 have separate medicinalchemistry departments, all of which grant a PhD degree inthis area of study. Of the approximately 40 new collegesand schools of pharmacy that have emerged since 2000,none has a separate medicinal chemistry department.17

Intellectual Domains of Medicinal Chemistry:Scopes and Importance in Pharmacy

The2 intellectual domains ofmedicinal chemistry thatare of value in pharmacy are drug design and developmentand ADMET (absorption, distribution, metabolism, excre-tion, and toxicity) assessments. Interpretation of mode ofaction at the molecular level and construction of SAR ofdrug molecules or biologically active compounds are im-portant scopes of the drug design and discovery domains,which in turn are vital facets of medicinal chemistry. Ad-ditionally, ADMET assessments of therapeutic drug clas-ses that have a significant influence on therapeutic decisionmaking are essential components of pharmacy education.As experts in the therapeutic use of medications and phar-maceutical care, pharmacists routinely provide therapeuticevaluations, recommendations, and counseling to patients

Table 1. The Study Objectives for Medicinal Chemistry in thePharm D Curriculum3

d Physico-chemical properties of drug molecules inrelation to drug ADME

d Chemical basis of pharmacology and therapeuticsd Fundamental pharmacophores for drugs used totreat disease

d Structure activity relationships in relation todrug-target interactions

d Chemical pathways of drug metabolismd Application to making drug therapy decisions


2

and other health care professionals regarding safe, appro-priate, and cost-effective use of medications. With currentemphasis on intense clinical training, pharmacists also areequipped with skills to evaluate scientific literature anddevelop evidence-based patient-specific pharmacotherapyplans. Thus, by offering a sound knowledge base of thechemical basis of drug action, its stability, SAR, mecha-nism of action, pharmacology, and ADMET, medicinalchemistry instills critical-thinking and problem-solvingskills in students that are essential for themaking of a com-petent pharmacist.

Medicinal Chemistry in Drug Design and DiscoveryA summary of important techniques and tools used in

drug design and discovery are listed in Table 2. Because adetailed discussion of these scientific techniques is beyondthe scope of this paper, interested readers are encouraged toread the sixth edition of Burger’sMedicinal Chemistry andDrug Discovery, Volume 1.18 We believe that a systematicreview of these scientific backgrounds during a pharma-cist’s educational years is fundamental to imparting athorough foundational knowledge and promotes lifelonglearning skills.

Medicinal chemists play a crucial role in driving thedrug discovery project by relying on their knowledge andexpertise in modern organic chemistry, biology of the dis-ease, in vitro and in vivo pharmacological screening, andpharmacokinetic characteristics, with the goal ofmaximiz-ing efficacy while minimizing side effects. Additionally, afirm understanding of ADMET issues related tomedicinesin the market for a target disease, regulatory affairs forsimilar drugs, drugs in the pipeline, scientific literature,and technological advances make the medicinal chemist

a vital part of the drug discovery team. Readers are directedto an extensive review of the historical perspective ofthe role of the medicinal chemist in drug discovery byLomberdino and Lowe III for more information.19 In thisarticle, we present a drug discovery case story below tohighlight themedicinal chemists’ role in the complex butexciting drug discovery process.

Drug Development Case Study: Developmentof Omeprazole.

In the late 1960s, a subdivision of AstraZeneca Re-search and Development started a research project to finddrugs capable of inhibiting gastric acid secretion for use inpatientswith peptic ulcer disease (Figure 1).20 The projectproduced a drug that was highly effective in rats but not inhumans. The project was abandoned for a time, but in1972 was revived, this time using a dog model.

A literature search identified a report by anotherpharmaceutical company of an antisecretory compoundpyridylthioacetamide. The second company dropped theproject because of the severe acute toxicity associated withthis drug. The observed toxicity was attributed to the thio-amide group and a decision to modify this group by incor-porating it into or in between heterocyclic ring systemswasmade. In 1973, a benzimidazole derivative, H124/26, wasdiscovered that had powerful antisecretory properties andlacked acute toxicity. The compound was patent protectedby a Hungarian company for use in tuberculosis; however,its sulfoxide metabolite (timoprazole) was not covered bythe patent, and in 1974 it was found to have even moreantisecretory potency than H124/26. Unfortunately, long-term toxicological studies revealed its ability to cause en-largement of the thyroid gland due to inhibition of iodineuptake. Through a literature search, the research team iden-tified substituted mercapto-benzimidazoles, which had noeffecton iodineuptake.When these substitutentswereaddedto timoprazole, the effects on thyroid and thymus glandswere eliminated without a reduction in the antisecretoryeffect of timoprazole. The most potent drug identified in1977, picoprazole, initially was associated with necrotiz-ing vasculitis in dogs; however, this effect was limited toone breed of beagle with antibodies to intestinal worms.This effect was not reproduced in other strains or in non-parasitized dogs; thus, picoprazole was given approval forinitial studies in humans and showed a good antisecretoryeffect with a long duration.20

About the same time as the picoprazole discovery(1977), the final step in acid secretion, the proton pump,was discovered. In the early 1980s, researchers found thatthe substituted benzimidazoles blocked the proton pumpprocess/action. Because weak bases exhibit a tendencyto accumulate in the acidic compartment, more electron

Table 2. Important Techniques Used in Drug Developmentand Medicinal Chemistry17

d Quantitative structure-activity relationship (QSAR)d Molecular modellingd Virtual screening and dockingd Drug target binding forcesd Combinatorial library designd Bioinformaticsd Structure based drug designd X-ray crystallographyd Nuclear Magnetic Resonance and Mass spectroscopyd Electron cryomicroscopy of biological macromoleculesd Peptidomimeticsd Analog designd Rational drug designd Chiralityd Study of structural basis for toxicityd Use of natural products as drug leads


3

donating substituents were added to the pyridine ring ofpicoprazole to increase its pKa and maximize its accumu-lation in parietal cells. The changes led to the identificationof omeprazole, with a pKa of 4.0 (about 1 unit higher thanpKaof picoprazole). Thehigher pKaalso increased the rateof acid-mediated conversion of this agent to its active spe-cies. The methoxy substitution in the benzimidozole ringalsomade the compoundmore stable to conversion at neu-tral pH.20 Subsequent clinical studies led to omeprazolemarketed as Prilosec (1989), the first among a new classof proton-pump inhibitors (PPIs), for the treatment of gas-tric acidity and ulcers.

Innovations in Medicinal Chemistry Education inAcademic Pharmacy

With evidence-based patient-centered care taking aprominent role in current pharmacy practice, creative waysto reinforce medicinal chemistry content are being activelypursuedby educators.Among these, structurally based ther-apeutic evaluation (SBTE), an innovative concept devel-oped by Alsharif and colleagues, uses knowledge of drugstructures in making therapeutic decisions and emphasizesthe relevance of medicinal chemistry to the pharmacist. All7 criteria of therapeutic decisionmaking (drug history/drugresponse, patient compliance, current medical history, pastmedical history, side effects, biopharmaceutics, and phar-macodynamics) are addressed in this SBTE approach andused by students to solve therapeutic problems for eachclass of drugs.21 Also, professional practice skills like prob-lem solving and decision-making, learning from problem-solving experiences, communicating, teaching, educating,and collaborating are reinforced by SBTE.22 SBTE hasproven to be a valuable tool for curriculum integrationand interdisciplinary teaching; as evidenced by student rec-ognition of medicinal chemistry as an extremely valuabletool for the scientific practice of pharmacy.23-25 The successof the SBTE approach clearly highlights that medicinalchemistry and pharmacy education are inseparable andare inherently bonded in their origin and future directions.

Partial replacement of the traditional lecture-basedteaching approach with problem-based learning consider-ably improved the problem-solving skills of medical stu-

dents by linking basic sciences to clinical practices.26 Thisled some medicinal chemistry educators to apply problem-based learning methodology in their teaching of medicinalchemistry content to pharmacy students. Medicinal chem-istry-based case studies were developed to solve clinicalproblems through group discussions. These case studiesled to a marked improvement in the problem-solving skillsof the students, reiterating the significance of medicinalchemistry as a critical component of pharmaceutical-caredirected learning.26-28 Roche and Zito developed comput-erized case studies emphasizing medicinal chemistry prin-ciples in the practice of pharmacy. Positive outcomes werereported for identifying relevant therapeutic problems, con-ducting thorough and mechanistic SAR analyses of drugproduct choices provided, evaluatingSARfindings in termsof patient needs anddesired therapeuticoutcomes, and solv-ing patient-related therapeutic problems.29,30 This teachingmethodology reinforced the indispensability of medicinalchemistry in the pharmacy curriculum. This method of in-struction also has been addressed in the SBTE approach.

Sound knowledge of functional group chemistry ofdrug molecules, along with ADMET parameters, is funda-mental to selection of appropriate agent and/or formulation,understanding of routes of drug administration, and dos-ages.31 Functional groups are critical to receptor binding,influence themodeof drug action, and serve as predictors oftheir potency. Accordingly, the development of computer-based tutorials containing structures, receptor biochemis-try, and functional group chemistry, has been amilestone inthe development of the technology-drivenmedicinal chem-istry instructional model for pharmacy curriculum. Indeed,evaluation of this instructionalmodel has revealed its over-whelmingly positive impact on pharmacy students’ perfor-mance.32 metabolic reactions are dependent on classicalchemical reactivity of the drugs’ functional groups andtheir local electronic and steric characteristics. Relyingon their knowledge of functional group chemistry (Figure2), the pharmacy student can comprehend reported drugmetabolites and rationally predict potential drug metabolicoutcomes.7 Such knowledge and expertise, critical to un-derstanding pharmacokinetic and pharmacodynamic char-acteristics of drugs, are unique to pharmacists and certainly

Figure 1. Development of Omeprazole.


4

derived from medicinal chemistry instruction in pharmacyschool.

DISCUSSIONA review of the evolution and progression of the

pharmacy profession reveals that the uniqueness of thisprofession is the pharmacist’s comprehensive expertise inmedicines and other pharmaceutical products comparedwith that of other health care professionals. Becausemed-icines are primarily chemical entities, early histories ofboth pharmacy and medicinal chemistry overlap and are in-herently bonded to each other. From the beginning of theacademic pharmacy program in theUnited States,medicinalchemistry has been an “indispensible” component of its cur-riculum.Thepharmacists’uniqueknowledgeofamedicine’sdesign, pharmacological action, manufacture, storage, use,supply, and handling has elevated the profession to its ap-propriate place in the health care sector. These areas of ex-pertise also led to legislation that increased the pharmacist’slegal role in patient care, the result of which is today’s phar-maceutical care. Pharmacists cannot afford to ignore theiridentity asmedication safety experts if theywant to success-fully perform and hold on to this assigned responsibility.

The interwoven nature of medicinal chemistry andpharmacy are evident in their origins (Appendix 1), as wellas in the important medicinal chemistry-related intellectualdomains. Being a competent pharmacist requires a soundknowledge of each of these domains. By embracing thediscipline ofmedicinal chemistry, the pharmacy professioncan reap enormous benefits. Medicinal chemistry, a uniquecomponent of the pharmacy curriculum, imparts vitalknowledge and critical-thinking skills to pharmacy studentsand sets them apart as chemical experts among health careprofessionals.33 This specialized set of proficiencies in me-dicinal chemistry anddrugdiscovery, poises the pharmacistas the leader of the health care team in efforts aimed atproviding patient-specific evidence-based care. Medici-nal chemists, as the entrepreneurs and innovators of ther-apeutic agents, the most important armor of health care,

play a critical role in sustaining the drug discovery anddevelopment process. The subject areas that are fundamen-tal to drug discovery also serve as sources for a completeknowledge base of the diseases and their safe andeconomictreatments. By encompassing these into the pharmacy cur-riculum, pharmacists become invaluable tomaintaining thehealth and well-being of the community.

The rigorous pharmacy curriculum is intended to im-part a sound knowledge base and prepare the pharmacystudent to play a central and a dynamic role among healthcare professionals post licensure. Medicinal chemistry,a key component of the pharmaceutical science founda-tion, plays a crucial role in the development of such a com-petency. The Pharmacy Practice Activity Classification bythe American Pharmacists Association recognizes phar-macist’s other historic roles in pharmaceutical industry,administration, regulatory agencies, professional associa-tions, public health, and academia.34 Thus, even fromahis-torical perspective, in addition to an interest in knowledgeenrichment about therapeutic agents, the significance ofdrug research and drug development in the pharmacy cur-riculum has never diminished, but rather increased.

CONCLUSIONThis article emphasizes the relevance of medicinal

chemistry in the pharmacy curriculum, its role in the evo-lution of pharmacy, and its paradigm shift to pharmaceu-tical care, as well as its history and intellectual domains.Medicinal chemistry provides a comprehensive under-standing of the underlying principles of drug action andbehaviorwithin the body,which is fundamental to today’spharmaceutical care and patient counseling. Because ap-prehensions regarding the relevance of medicinal chemis-try continue to exist, a change in the approach to howmedicinal chemistry content is presented is necessary tobetter fit this basic science into the pharmacy curriculumunder the newly set goals. Some educators are alreadyengaged in this endeavour. Future research/reviews shouldaddress the scope of medicinal chemistry in the pharmacy

Figure 2. Identification of functional groups showing few common metabolic routes; phase I: (1) ester hydrolysis by esterases, (2)N-dealkylation by CYP enzymes, (3) O-delakylation by CYPs, (4) p-hydroxylation by CYPs; relative rates are: (1) .. (2) . (3);(4); phase II: (5) glucuronidation (or sulphate conjugation), (6) N-acetylation; relative rates are: (5) .. (6). (Adopted from7)


5

curriculum with appropriate drug class examples. Histori-cally,medicinal chemistry has developedhand-in-handwiththepharmacyprofessionandhas alwaysbeenat the forefrontof drug design and discovery. The components of drug de-sign and discovery contribute to the pharmacy student’sfoundational knowledge base and will have a tremendousimpact in advancing the professional leadership of a phar-macist in the pharmaceutical and health care sectors.

ACKNOWLEDGEMENTSThe authors wish to thank Dr. Gayle Brazeau, Dean,

University of NewEngland College of Pharmacy, for hercareful review and constructive suggestions in the manu-script preparation. The authors are indebted to KimberlyLindsey, PharmD, BCPS, for a critical review of themanuscript.

REFERENCES1. Higby GJ. Evolution of pharmacy. In: Troy DB, ed. Remington:The Science and Practice of Pharmacy, 21st ed. Philadelphia, PA:Lippincott Williams & Wilkins; 2006:7-19.2. Hepler CD, Strand IM. Opportunities and responsibilities inpharmaceutical care. Am J Hosp Pharm. 1990;47(3):533-543.3. Accreditation Standard for Continuing Pharmacy Education,Accreditation Council for Pharmacy Education. http://www.acpe-accredit.org/pdf/ACPE_Revised_PharmD_Standards_Adopted_Jan152006.pdf. Accessed August 15, 2011.4. Ceresia GB, Brusch CA. An introduction to the history ofmedicinal chemistry. Am J Pharm Sci Support Public Health.1955;127(11):384-395.5. Brown CE. Some relations of early chemistry in America tomedicine. J Chem Educ. 1926;3(3):267-279.6. Burger A. History and economics of medicinal chemistry. In:Burger A, ed. Medicinal Chemistry, 3rd ed. Vol 1. John Wiley &Sons; 1970:4-19.7. Erhardt PW, Proudfoot JR. Drug discovery: historical perspective,current status, and outlook. Compr Med Chem II. 2007;1:29-96.8. Witebsky E. Ehrlich’s side chain theory in the light of presentimmunology. Ann NY Acad Sci. 1954;59(2):168-181.9. Maehle AH, Prull CR, Halliwell RF. The emergence of drugreceptor theory. Nat Rev Drug Discov. 2002;1(8):637-641.10. Korolkovas A. Essentials of Medicinal Chemistry 2nd ed. NewYork, NY: John Wiley & Sons, Inc.; 1988.11. Merrifield RB. Solid phase peptide synthesis I: the synthesis ofa tetrapeptide. J Am Chem Soc. 1963;85(14):2149-2154.12. Geyson HM, Meloen RH, Barteling SJ. Use of peptide synthesisof probe viral antigens for epitopes to a resolution of single aminoacid. Proc Natl Acad Sci USA. 1984;81(13):3998-4002.13. Dooley CT, Houghten RA. The use of positional scanningsynthetic peptide combinatorial libraries for the rapid determinationof opioid receptor ligands. Life Sci. 1993;52(18):1509-1517.14. Freier SM, Konings DAM, Wyatt JR, Ecker DJ. Deconvolutionof combinatorial libraries for drug discovery: a model system. J MedChem. 1996;39(14):2720-2726.

15. Xiang X-D, Sun X, Briceno G, Lou Y, Wang K-A, Chang H,Wallace-Freedman WG, Chen S-W, Schultz PG. A combinatorialapproach to materials discovery. Science. 1995;268(5218):1738-1740.16. Timmerman H. Reflection of medicinal chemistry since the1950s. Compr Med Chem II. 2007;8:7-15.17. AACP Institutional Members. http://www.aacp.org/about/membership/institutionalmembership/Pages/usinstitutionalmember.aspx. Accessed August 15, 2011.18. Burger A. Burger’s Medicinal Chemistry Vol 1. 6th ed. Hoboken,NJ:John Wiley & Sons, Inc.; 2003.19. Lomberdino JG, Lowe III JA. The role of medicinal chemist indrug discovery – then and now. Nat Rev Drug Discov. 2004;3(10):853-862.20. Olbe L, Carlsson E, Lindberg P. A proton-pump inhibitorexpedition: the case histories of omeprazole and esomeprazole. NatRev Drug Discov. 2003;2(2):132-139.21. Alsharif NZ, Theesen KA, Roche VF. Structurally basedtherapeutic evaluation: a therapeutic and practical approach toteaching medicinal chemistry. Am J Pharm Educ. 1997;61(1):55-60.22. Alsharif NZ, Destache CJ, Roche VF. Teaching MedicinalChemistry to meet outcome objectives for pharmacy education. AmJ Pharm Educ. 1999;63(1):34-40.23. Alsharif NZ, Shara MA, Roche VF. The structurally-basedtherapeutic evaluation (SBTE) concept: an opportunity forcurriculum integration and interdisciplinary teaching. Am J PharmEduc. 2001;65:314-323.24. Alsharif NZ, Galt KA, Ahmed M, Chapman R, OgunbadeniyiAM. Instructional model to teach clinically relevant medicinalchemistry. Am J Pharm Educ. 2006;70(4):Article 91.25. Alsharif NZ, Galt KA. Evaluation of an instructional model toteach clinically relevant Medicinal Chemistry in a campus anda distance pathway. Am J Pharm Educ. 2008;72(2):Article 31.26. Herrier RN, Jackson TR, Consroe PF. The use of student-centered, problem based, clinical case discussions to enhancelearning in pharmacology and medicinal chemistry. Am J PharmEduc. 1997;61(4):441-446.27. Currie BL, Roche VF, Zito SW.Medicinal Chemistry Case StoryWorkbook. Baltimore, MD: Williams & Wilkins; 1996.28. Dimmock JR. Problem-solving learning: applications inmedicinal chemistry. Am J Pharm Educ. 2000;64(1):44-49.29. Roche VF, Zito SW. Computerized Medicinal Chemistry casestudies. Am J Pharm Educ. 1997;61(4):447-452.30. Roche VF, Aitken MJ, Zito SW. Evaluation of computerizedMedicinal Chemistry case study modules as tools to enhance studentlearning and clinical problem-solving skills. Am J Pharm Educ.1999;63(3):289-295.31. Harrold MW. Importance of functional group chemistry in the drugselection process: a case study. Am J Pharm Educ. 1998;62(2):213-218.32. Harrold MW, Newton GD. Development and Evaluation ofcomputer-based tutorials in biochemistry and medicinal chemistry.Am J Pharm Educ. 1998;62(1):22-30.33. Roche VF, Davis PJ, Pankaskie MC, et al. The status ofchemistry content in the professional pharmacy curriculum: resultsof a national survey. Am J Pharm Educ. 2000;64(3):239-251.34. Pharmacy Practice Activity Classification (PPAC), AmericanPharmacists Association. http://www.pharmacist.com/. AccessedAugust 15, 2011.


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Appendix

1.Relationship

BetweentheHistory

ofDrugDiscoveryandDevelopment,Medicinal

Chem

istry,andPharmacy1-16

History

ofDrugDiscoveryandDevelopment

2735B.C.

1600B.C.

400B.C.

1200s

1500s

1600-1800

1800s

1900s

1.Chinese

scholar-em

peror

ShengNung:

ch’angshangto

treatmalaria

Egyptian

medicine:

vegetable

origin

Hippocrates,

Discarides,

Pliny,Galen:

metallicsalts

andgalenicals

1.Alchem

ists:

senna,

camphor,

rhubarb,tamarind,

nutm

egwere

described

inArabianmedical

treatise

Firsthalfofthis

century:

Paracelsus:Father

oftoday’s

medicinal/

pharmaceutical

chem

istryto

preparemedicine

1.Isolationof

benzoic

acid

and

ephedrine(1887)

paved

new

dim

ensionin

drug

discoveryfrom

plantorigin

1.Salicylicacid

synthesisbyKolbe

(mid-19thcentury),

synthetic

dyes

by

Perkin

(1856),

aspirin

byDresser

(1889)arethe

milestonesin

modern

drug

discovery

1.Synthesisofbarbital

byFischer

and

Mering(1903)

2.Babylonian-

Assyrian

culture:250

vegetable

drugs

2.1240:German

Emperor

FrederickII:

Issued

Magna

Chartaof

medicinal

chem

ist

2.Synthesisof

ureapaved

the

new

toolofdrug

discovery

2.Ehrlich’s

“Side

chaintheory”(1885)

andchem

otherapy

(1891);Fischer’s

lock-and-key

theory

(1894)are

important

advancementsin

drugdesignand

discovery.

2.Henry’s

hypothesis

onenzyme-substrate

complex(1903)

3.Grimm’s

and

Erlenmeyer’s

concepts

ofisosterism

and

bioisosterism

(1929-1931)

4.Chargetransfer

bykosower

(1955),induced-fit

theory

byKoshland

(1958),drug

latentiationbyHarper

(1959)andprodrugby

Albert(1960),

Hansch’s

QSAR

(1960s)

and

artificial

intelligence

indrugresearch

by

Chu(1974)

(Continued)


7

Appendix

1.(C

ontinued

)

History

ofDrugDiscoveryandDevelopment

2735B.C.

1600B.C.

400B.C.

1200s

1500s

1600-1800

1800s

1900s

5.Purificationof

insulinbyBenting

andBest(1922),

isolationofpenicillin

byFleming(1929),

discoveryofsulfa

antibacterialsby

Trefouel,Nittiand

Bovet

(1935)andtotal

synthesisofinsulinby

Kam

der

etal.(1975)

6.Solidphaseorganic

synthesis(1960s)

and

Merrifield’s

Nobel

prizeforthisdiscovery

in1984,combinatorial

chem

istryby

Geysen

etal.(1984)

andhigh

throughput

screening,

molecular

modeling

andrationaldrug

design

History

ofMedicinalChem

istry

2735B.C.

1600B.C.

400B.C.

1200s

1500-1550

1600-1800

1800s

1900s

1.Chinese

scholar-

emperorSheng

Nung:ch’ang

shangto

treat

malaria

Egyptian

medicine:

vegetable

origin

Hippocrates,

Discarides,

Pliny,Galen:

metallicsalts

andgalenicals

1.Alchem

ists:

Contributedto

develop

medicinal

chem

istry

Paracelsus:Father

oftoday’s

medicinal/

pharmaceutical

chem

istryto

preparemedicine

1.Isolationof

benzoic

acid

and

ephedrinearethe

milestones

inmedicinal

chem

istry

1.Both

milestones

1and2aboveare

also

considered

the

important

milestones

formedicinal

chem

istryera

1.Themilestones

mentioned

inthedrugdesign

anddevelopment

above(1-6)are

also

considered

important

milestones

inthe

modernmedicinal

chem

istry.

(Continued)


8

Appendix

1.(C

ontinued

)

History

ofMedicinalChem

istry

2735B.C.

1600B.C.

400B.C.

1200s

1500-1550

1600-1800

1800s

1900s

2.Babylonian-

Assyrian

culture:250

vegetable

drugs

2.German

Emperor

FrederickII:

Issued

Magna

Chartaof

medicinal

chem

ist

2.Synthesisof

urea,

thebirth

of

new

science

of

organic

medicinal

chem

istry

2.Thisisindeedthe

birth

periodof

modernmedicinal

chem

istrywiththe

inclusionof

Ehrlich’s

“Side

chaintheory”and

chem

otherapyand

Fischer’s

lock-and-

key

theory

2.Medicinal

chem

istryreceived

form

alrecognition

inacadem

icpharmacyin

1932

3.American

Chem

ical

Society

started

Divisionof

Pharmaceutical

Chem

istry

(1909-1920),

then

Division

ofMedicinal

Products(1920-

1948),which

finally

tookthe

nam

eofDivision

ofMedicinal

Chem

istryin

1948.

History

ofPharm

acy,Academ

icPharm

acy

andMedicinalChem

istryin

Academ

icPharm

acy

2735B.C.

1600B.C.

400B.C.

1100s

1500-1550

1600-1800

1800s

1900s

1.Chinese

scholar-

emperorSheng

Nung:ch’ang

shangto

treat

malaria

Egyptian

medicine:

vegetable

origin

–Exam

plesof

ancient

apothecary

Hippocrates,

Discarides,

Pliny,Galen:

metallicsalts

andGalenicals–

exam

plesof

apothecary/

pharmacy

Publicpharmacy

began

inItaly,

France

and

elsewhere

Paracelsus:Father

ofpreparing

medicinethat

apharmacydoes.

Essentially

the

sameas

the

medicinal

chem

istry

1777:thefirst

pharmacy

school

inFrance

1.Philadelphia

College

ofPharmacy–the

firstinstitute

for

awardingpharmacy

Diplomain

America

in1821.

1.4-Y

earB.S.Pharmacy

degreeas

therequirem

ent

forpharmacylicensure

intheU.S.in

1932,with

medicinal

chem

istryas

anessential

componentin

itscurriculum.

(Continued)


9

Appendix

1.(C

ontinued

)

History

ofPharm

acy,Academ

icPharm

acy

andMedicinalChem

istryin

Academ

icPharm

acy

2735B.C.

1600B.C.

400B.C.

1100s

1500-1550

1600-1800

1800s

1900s

2.Babylonian-

Assyrian

culture:250

vegetable

drugs

Theseare

exam

plesof

ancient

apothecary

2.William

Proctor

Jr.defined

pharmacy

in1869as

the“art

ofpreparingand

dispensingmedicine”

2.University

ofSouthern

California

startedfirst6-Y

ear

(21

4)DoctorofPharmacy

(Pharm.D.)degreein

1960,

whilemostinstitutes

selected

5-year(2

13)B.S.

Pharmacydegreeas

standard

withmedicinal

chem

istryand

pharmaceutics

asthecore

requirem

ents.

3.The“Paradigm

Shift”:

OmnibusBudget

ReconciliationAct

1990

(OBRA

1990)increased

theresponsibilityof

pharmacistsbyincorporating

thekey

conceptof

“PharmaceuticalCare”

asthemajorrole

ofpharmacist.

4.6-Y

ear(2

14)Pharm.D.

degreebecam

ethestandard

requirem

entforpharmacy

licensure

allover

theU.S.

toachievethedesired

outcome

bytheparadigm

shift.

5.ACPEStandard13

(Curriculum

Core

–Knowledge,

Skills,

Attitudes,andValues)has

clearlystated

theneedof

medicinal

chem

istryin

Pharm.D.curriculum

inits

revised

appendix

Beffective

since

2007.


10

Documents

Medicinal Chemistry and the Pharmacy Curriculum