Medicinal Chemistry and the Pharmacy Curriculum

Abstract

The origins and advancements of pharmacy, medicinal chemistry, and drug discovery are interwoven in nature. Medicinal chemistry provides pharmacy students with a thorough understanding of drug mechanisms of action, structure-activity relationships (SAR), acid-base and physicochemical properties, and absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles. A comprehensive understanding of the chemical basis of drug action equips pharmacy students with the ability to answer rationally the “why” and “how” questions related to drug action and it sets the pharmacist apart as 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-solving skills to pharmacy students, enabling them to make optimal patient-specific therapeutic decisions. This review highlights the parallel nature of the history of pharmacy and medicinal chemistry, as well as the key elements of medicinal chemistry and drug discovery that make it an indispensable component of the pharmacy curriculum.

INTRODUCTION

It was not until the mid 19^th century that pharmacy emerged as a professional entity in the United States. In 1869, William Proctor Jr defined pharmacy as the “art of preparing and dispensing medicine” which “embodies the knowledge and skill requisite to carry them out to practice.”¹ Thus, preparation and dispensing have been at the heart of pharmacy practice since the beginning of the profession, with sound knowledge of chemical compatibility, solubility, and stability of the drugs deemed essential to effectively accomplish the “preparation” component of the prescription.¹

Over the last 4 decades, the role of a pharmacist progressively shifted from being a compounder and supplier of pharmaceutical products to a service and information provider, and eventually to a comprehensive patient care provider.² In 1990, Hepler and Strand called for a paradigm shift to “pharmaceutical care,” a concept that is defined as “the responsible provision of drug therapy for the purpose of achieving definite outcomes that improve a patient's quality of life.”² The Omnibus Budget Reconciliation Act of 1990 (OBRA 1990) increased the clinical responsibility of pharmacists by requiring them to counsel Medicaid patients and participate in prospective and retrospective drug utilization review programs. Responding to this challenge, US colleges and schools of pharmacy moved toward offering the PharmD program.¹

The advent of this new direction for the pharmacy profession prompted an increase in the clinical coursework in the pharmacy curriculum. Unfortunately, this paradigm shift also initiated a debate over the relevance of medicinal chemistry, a basic pharmaceutical science, in pharmacy education. The Accreditation Council for Pharmacy Education (ACPE) Standard No. 13 clearly states the need to provide a thorough scientific foundation for the achievement of desired professional outcomes.³ To achieve this goal, ACPE requires the curriculum to contain biomedical sciences, pharmaceutical sciences, social/behavioral/administrative sciences, and clinical sciences.³ Additional guidelines specify the medicinal chemistry requirements under the umbrella of pharmaceutical sciences (Table 1).

Table 1.

The Study Objectives for Medicinal Chemistry in the Pharm D Curriculum³

Important historic milestones and the interrelationship between drug discovery and development, medicinal chemistry, and the pharmacy profession are highlighted in the table in Appendix 1.^4-16 While drug development and medicinal chemistry are purely scientific, the pharmacy profession deals with the art of preparing and dispensing as well as providing optimal pharmaceutical care with therapeutic agents. In pharmacy, the hallmark of the new millennium has been the tremendous advancements made in the area of pharmacogenomics, whereby dosages of medications are tailored to individual patients based on specific genomic patterns, polymorphisms, and therapeutic responses to select drugs. Thus, pharmacogenomics is a rapidly developing area that lends the application of biotechnology principles to the efficient practice of pharmacy.

HISTORY OF MEDICINAL CHEMISTRY

From a fertile mix of ancient folk medicine and early natural-product chemistry, medicinal chemistry emerged about 150 years ago as a distinct discipline. This area of study received formal recognition 78 years ago with its inclusion in the 4-year BSPharm degree curriculum.^1,6 The 19^th century may be viewed as the birth period of modern medicinal chemistry with the introduction of side chain theory of drug action in 1885 by Berlin immunologist Ehrlich.⁸ Later in 1891, he coined the term chemotherapy and defined it as “the chemical entities exhibiting selective toxicities against particular infectious agent.”⁴ The modern drug receptor theory originated from this side chain theory, which was supported during the same period (mid-1890s) by Cambridge physiologist Langley who described it in his publications as “receptive substances.” The importance of receptors for understanding diverse biological processes was recognized initially by Ehrlich and Langley and then followed by Clark in the 1930s. Research on enzyme specificity (lock-and-key theory) by Fischer in 1894 and Henry's hypothesis on enzyme-substrate complex formation in 1903 are recognized as key advancements in the principles of drug action and modern medicinal chemistry.⁹ Grimm's and Erlenmeyer's concepts of isosterism and bioisoterism (1929-1931) also had a tremendous impact on the understanding of structure activity relationship (SAR) of drugs and development of modern medicinal chemistry.⁷ Other notable advancements in understanding of drug action and design that were made in the mid to late 20^th 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 mathematical methods to medicinal chemistry and transformation of SAR studies into quantitative SAR (QSAR) (Hansch and others, 1960s); and application of artificial intelligence to drug research (Chu, 1974).¹⁰

Medicinal chemistry is defined as an interdependent mature science that is a combination of applied (medicine) and basic (chemistry) sciences. It encompasses the discovery, development, identification, and interpretation of the mode of action of biologically active compounds at the molecular level. Medicinal chemistry may be viewed as the melting pot of synthetic chemistry and molecular pharmacology that emphasizes the study of SAR of drug molecules; it therefore requires a clear understanding of both chemical and pharmacological principles. At an institutional level in the United States, medicinal chemistry first started 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 medicinal chemistry, from the American Chemical Society.¹⁶

Medicinal chemistry continues to play a major role in drug research and development, taking advantage of newer techniques and increased knowledge of different branches of related sciences. The roots of modern medicinal chemistry, however, lie in all branches of chemistry and biology, which began its journey in the battle against diseases in the revered hands of Ehrlich who dreamed of a “magic bullet” to combat all infectious diseases. Out of 114 US colleges and schools of pharmacy, 20 have separate medicinal chemistry departments, all of which grant a PhD degree in this area of study. Of the approximately 40 new colleges and 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

The 2 intellectual domains of medicinal chemistry that are of value in pharmacy are drug design and development and ADMET (absorption, distribution, metabolism, excretion, and toxicity) assessments. Interpretation of mode of action at the molecular level and construction of SAR of drug molecules or biologically active compounds are important scopes of the drug design and discovery domains, which in turn are vital facets of medicinal chemistry. Additionally, ADMET assessments of therapeutic drug classes that have a significant influence on therapeutic decision making are essential components of pharmacy education. As experts in the therapeutic use of medications and pharmaceutical care, pharmacists routinely provide therapeutic evaluations, recommendations, and counseling to patients and other health care professionals regarding safe, appropriate, and cost-effective use of medications. With current emphasis on intense clinical training, pharmacists also are equipped with skills to evaluate scientific literature and develop evidence-based patient-specific pharmacotherapy plans. Thus, by offering a sound knowledge base of the chemical basis of drug action, its stability, SAR, mechanism of action, pharmacology, and ADMET, medicinal chemistry instills critical-thinking and problem-solving skills in students that are essential for the making of a competent pharmacist.

Medicinal Chemistry in Drug Design and Discovery

A summary of important techniques and tools used in drug design and discovery are listed in Table 2. Because a detailed discussion of these scientific techniques is beyond the scope of this paper, interested readers are encouraged to read the sixth edition of Burger's Medicinal Chemistry and Drug Discovery, Volume 1.¹⁸ We believe that a systematic review of these scientific backgrounds during a pharmacist's educational years is fundamental to imparting a thorough foundational knowledge and promotes lifelong learning skills.

Table 2.

Important Techniques Used in Drug Development and Medicinal Chemistry¹⁷

Medicinal chemists play a crucial role in driving the drug discovery project by relying on their knowledge and expertise in modern organic chemistry, biology of the disease, in vitro and in vivo pharmacological screening, and pharmacokinetic characteristics, with the goal of maximizing efficacy while minimizing side effects. Additionally, a firm understanding of ADMET issues related to medicines in the market for a target disease, regulatory affairs for similar drugs, drugs in the pipeline, scientific literature, and technological advances make the medicinal chemist a vital part of the drug discovery team. Readers are directed to an extensive review of the historical perspective of the role of the medicinal chemist in drug discovery by Lomberdino and Lowe III for more information.¹⁹ In this article, we present a drug discovery case story below to highlight the medicinal chemists’ role in the complex but exciting drug discovery process.

Drug Development Case Study: Development of Omeprazole.

In the late 1960s, a subdivision of AstraZeneca Research and Development started a research project to find drugs capable of inhibiting gastric acid secretion for use in patients with peptic ulcer disease (Figure 1).²⁰ The project produced a drug that was highly effective in rats but not in humans. The project was abandoned for a time, but in 1972 was revived, this time using a dog model.

Figure 1.

Development of Omeprazole.

A literature search identified a report by another pharmaceutical company of an antisecretory compound pyridylthioacetamide. The second company dropped the project because of the severe acute toxicity associated with this drug. The observed toxicity was attributed to the thioamide group and a decision to modify this group by incorporating it into or in between heterocyclic ring systems was made. In 1973, a benzimidazole derivative, H124/26, was discovered that had powerful antisecretory properties and lacked acute toxicity. The compound was patent protected by a Hungarian company for use in tuberculosis; however, its sulfoxide metabolite (timoprazole) was not covered by the patent, and in 1974 it was found to have even more antisecretory potency than H124/26. Unfortunately, long-term toxicological studies revealed its ability to cause enlargement of the thyroid gland due to inhibition of iodine uptake. Through a literature search, the research team identified substituted mercapto-benzimidazoles, which had no effect on iodine uptake. When these substitutents were added to timoprazole, the effects on thyroid and thymus glands were eliminated without a reduction in the antisecretory effect of timoprazole. The most potent drug identified in 1977, picoprazole, initially was associated with necrotizing vasculitis in dogs; however, this effect was limited to one breed of beagle with antibodies to intestinal worms. This effect was not reproduced in other strains or in nonparasitized dogs; thus, picoprazole was given approval for initial studies in humans and showed a good antisecretory effect 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 that the substituted benzimidazoles blocked the proton pump process/action. Because weak bases exhibit a tendency to accumulate in the acidic compartment, more electron donating substituents were added to the pyridine ring of picoprazole to increase its pKa and maximize its accumulation in parietal cells. The changes led to the identification of omeprazole, with a pKa of 4.0 (about 1 unit higher than pKa of picoprazole). The higher pKa also increased the rate of acid-mediated conversion of this agent to its active species. The methoxy substitution in the benzimidozole ring also made the compound more stable to conversion at neutral pH.²⁰ Subsequent clinical studies led to omeprazole marketed as Prilosec (1989), the first among a new class of proton-pump inhibitors (PPIs), for the treatment of gastric acidity and ulcers.

Innovations in Medicinal Chemistry Education in Academic Pharmacy

With evidence-based patient-centered care taking a prominent role in current pharmacy practice, creative ways to reinforce medicinal chemistry content are being actively pursued by educators. Among these, structurally based therapeutic evaluation (SBTE), an innovative concept developed by Alsharif and colleagues, uses knowledge of drug structures in making therapeutic decisions and emphasizes the relevance of medicinal chemistry to the pharmacist. All 7 criteria of therapeutic decision making (drug history/drug response, patient compliance, current medical history, past medical history, side effects, biopharmaceutics, and pharmacodynamics) are addressed in this SBTE approach and used by students to solve therapeutic problems for each class of drugs.²¹ Also, professional practice skills like problem solving and decision-making, learning from problem-solving experiences, communicating, teaching, educating, and collaborating are reinforced by SBTE.²² SBTE has proven to be a valuable tool for curriculum integration and interdisciplinary teaching; as evidenced by student recognition of medicinal chemistry as an extremely valuable tool for the scientific practice of pharmacy.^23-25 The success of the SBTE approach clearly highlights that medicinal chemistry and pharmacy education are inseparable and are inherently bonded in their origin and future directions.

Partial replacement of the traditional lecture-based teaching approach with problem-based learning considerably improved the problem-solving skills of medical students by linking basic sciences to clinical practices.²⁶ This led some medicinal chemistry educators to apply problem-based learning methodology in their teaching of medicinal chemistry content to pharmacy students. Medicinal chemistry-based case studies were developed to solve clinical problems through group discussions. These case studies led to a marked improvement in the problem-solving skills of the students, reiterating the significance of medicinal chemistry as a critical component of pharmaceutical-care directed learning.^26-28 Roche and Zito developed computerized case studies emphasizing medicinal chemistry principles in the practice of pharmacy. Positive outcomes were reported for identifying relevant therapeutic problems, conducting thorough and mechanistic SAR analyses of drug product choices provided, evaluating SAR findings in terms of patient needs and desired therapeutic outcomes, and solving patient-related therapeutic problems.^29,30 This teaching methodology reinforced the indispensability of medicinal chemistry in the pharmacy curriculum. This method of instruction also has been addressed in the SBTE approach.

Sound knowledge of functional group chemistry of drug molecules, along with ADMET parameters, is fundamental to selection of appropriate agent and/or formulation, understanding of routes of drug administration, and dosages.³¹ Functional groups are critical to receptor binding, influence the mode of drug action, and serve as predictors of their potency. Accordingly, the development of computer-based tutorials containing structures, receptor biochemistry, and functional group chemistry, has been a milestone in the development of the technology-driven medicinal chemistry instructional model for pharmacy curriculum. Indeed, evaluation of this instructional model has revealed its overwhelmingly positive impact on pharmacy students’ performance.³² metabolic reactions are dependent on classical chemical reactivity of the drugs’ functional groups and their local electronic and steric characteristics. Relying on their knowledge of functional group chemistry (Figure 2), the pharmacy student can comprehend reported drug metabolites and rationally predict potential drug metabolic outcomes.⁷ Such knowledge and expertise, critical to understanding pharmacokinetic and pharmacodynamic characteristics of drugs, are unique to pharmacists and certainly derived from medicinal chemistry instruction in pharmacy school.

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)

DISCUSSION

A review of the evolution and progression of the pharmacy profession reveals that the uniqueness of this profession is the pharmacist's comprehensive expertise in medicines and other pharmaceutical products compared with that of other health care professionals. Because medicines are primarily chemical entities, early histories of both pharmacy and medicinal chemistry overlap and are inherently bonded to each other. From the beginning of the academic pharmacy program in the United States, medicinal chemistry has been an “indispensible” component of its curriculum. The pharmacists’ unique knowledge of a medicine's design, pharmacological action, manufacture, storage, use, supply, and handling has elevated the profession to its appropriate place in the health care sector. These areas of expertise also led to legislation that increased the pharmacist's legal role in patient care, the result of which is today's pharmaceutical care. Pharmacists cannot afford to ignore their identity as medication safety experts if they want to successfully perform and hold on to this assigned responsibility.

The interwoven nature of medicinal chemistry and pharmacy are evident in their origins (Appendix 1), as well as in the important medicinal chemistry-related intellectual domains. Being a competent pharmacist requires a sound knowledge of each of these domains. By embracing the discipline of medicinal chemistry, the pharmacy profession can reap enormous benefits. Medicinal chemistry, a unique component of the pharmacy curriculum, imparts vital knowledge and critical-thinking skills to pharmacy students and sets them apart as chemical experts among health care professionals.³³ This specialized set of proficiencies in medicinal chemistry and drug discovery, poises the pharmacist as the leader of the health care team in efforts aimed at providing patient-specific evidence-based care. Medicinal chemists, as the entrepreneurs and innovators of therapeutic agents, the most important armor of health care, play a critical role in sustaining the drug discovery and development process. The subject areas that are fundamental to drug discovery also serve as sources for a complete knowledge base of the diseases and their safe and economic treatments. By encompassing these into the pharmacy curriculum, pharmacists become invaluable to maintaining the health and well-being of the community.

The rigorous pharmacy curriculum is intended to impart a sound knowledge base and prepare the pharmacy student to play a central and a dynamic role among health care professionals post licensure. Medicinal chemistry, a key component of the pharmaceutical science foundation, plays a crucial role in the development of such a competency. The Pharmacy Practice Activity Classification by the American Pharmacists Association recognizes pharmacist's other historic roles in pharmaceutical industry, administration, regulatory agencies, professional associations, public health, and academia.³⁴ Thus, even from a historical perspective, in addition to an interest in knowledge enrichment about therapeutic agents, the significance of drug research and drug development in the pharmacy curriculum has never diminished, but rather increased.

CONCLUSION

This article emphasizes the relevance of medicinal chemistry in the pharmacy curriculum, its role in the evolution of pharmacy, and its paradigm shift to pharmaceutical care, as well as its history and intellectual domains. Medicinal chemistry provides a comprehensive understanding of the underlying principles of drug action and behavior within the body, which is fundamental to today's pharmaceutical care and patient counseling. Because apprehensions regarding the relevance of medicinal chemistry continue to exist, a change in the approach to how medicinal chemistry content is presented is necessary to better fit this basic science into the pharmacy curriculum under the newly set goals. Some educators are already engaged in this endeavour. Future research/reviews should address the scope of medicinal chemistry in the pharmacy curriculum with appropriate drug class examples. Historically, medicinal chemistry has developed hand-in-hand with the pharmacy profession and has always been at the forefront of drug design and discovery. The components of drug design and discovery contribute to the pharmacy student's foundational knowledge base and will have a tremendous impact in advancing the professional leadership of a pharmacist in the pharmaceutical and health care sectors.

Appendix 1.

Relationship Between the History of Drug Discovery and Development, Medicinal Chemistry, and Pharmacy^1-16