PHAR 303 PHARMACEUTICAL CHEMISTRY I Suggested sources: Foye’s Principles of Medicinal Chemistry, lecture notes, internet services Outline of the source:

What is Medicinal Chemistry? Medicinal chemistry is the chemistry discipline concerned with the design, development and synthesis of pharmaceutical drugs. The discipline combines expertise from chemistry and pharmacology to identify, develop and synthesize chemical agents that have a therapeutic use and to evaluate the properties of existing drugs.

Med Chem research areas Drug candidate design (discovery) Drug and drug candidate synthesis (discovery) Structure identification (discovery) Drug metabolism studies Pharmacological activity screening Chemical basis of drug bioactivation Chemical Targeting

A few words on historical development The removal of spiritual believes in people’s minds and thinking scientifically clearly acclerated the development of various science including medicinal chemistry. The source of folk medicine: The oldest records of the use of therapeutic plants and minerals are derived from the ancient civilizations of the Chinese, the Hindus, the Mayans of Central America, and the Mediterranean peoples of antiquity. The 19th Century: The 19th century saw a great expansion in the knowledge of chemistry, which greatly extended the herbal pharmacopeia that had previously been established. The 20th Century: The development of pharmaceutical industry and medicinal chemistry.

A few words on historical development The 19th 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. Later in 1891, he coined the term chemotherapy and defined it as “the chemical entities exhibiting selective toxicities against particular infectious agent. 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.” 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. 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.

A few words on historical development Other notable advancements in understanding of drug action and design that were made in the 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 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).

What is now for med chem? 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.

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.

Drug Discovery from Natural Products Historically, the majority of new drugs have been generated from natural products (secondary metabolites) and from compounds derived from natural products. Natural products and their derivatives have been and continue to be rich sources for drug discovery. However, natural products are not drugs. They are produced in nature and through biological assays they are identified as leads, which become candidates for drug development. More than 60% of the drugs that are in the market derive from natural sources. During the last two decades, research aimed at exploiting natural products as a resource has seriously declined. This is in part due to the development of new technologies such as combinatorial chemistry, metagenomics and high-throughput screening.

Medicinal Plants in Folklore The use of natural products as medicines has been described throughout history in the form of traditional medicines, remedies, potions and oils with many of these bioactive natural products still being unidentified. The dominant source of knowledge of natural product uses from medicinal plants is a result of man experimenting by trial and error for hundreds of centuries through palatability trials or untimely deaths, searching for available foods for the treatment of diseases. This is the main topic of Pharmacognosy. More specific examples afre given in the related lecture series.

Primary and Secondary Metabolites (Natural Products) The biosynthesis and breakdown of proteins, fats, nucleic acids and carbohydrates, which are essential to all living organisms, is known as primary metabolism with the compounds involved in the pathways known as “primary metabolites”. The mechanism by which an organism biosynthesizes compounds called ‛secondary metabolites’ (natural products) is often found to be unique to an organism or is an expression of the individuality of a species and is referred to as “secondary metabolism”. Secondary metabolites are generally not essential for the growth, development or reproduction of an organism and are produced either as a result of the organism adapting to its surrounding environment or are produced to act as a possible defense mechanism against predators to assist in the survival of the organism.

Some examples on Historically Important Natural Products Acetylsalicyclic acid (1), Salicin (2), Morphine (3), Digitoxin (4), Quinine (5) Pilocarpine (6). Acetylsalicyclic acid (1) (aspirin) derived from the natural product, salicin (2) isolated from the bark of the willow treeSalix alba L. Investigation of Papaver somniferum L. (opium poppy) resulted in the isolation of several alkaloids including morphine (3), Digitalis purpurea L. Has the active constituent digitoxin (4), a cardiotonic glycoside that enhances cardiac conduction, thereby improving the strength of cardiac ontractibility The anti-malarial drug quinine (5) isolated from the bark of Cinchona succirubra Pilocarpine (6) found in Pilocarpus jaborandi (Rutaceae) is an L-histidine-derived alkaloid, which has been used in the treatment of chronic open-angle glaucoma.

Preparation of Initial Extracts and Preliminary Biologic Screening It is typical to extract initially terrestrial plants with a polar solvent like methanol or ethanol, and then subject this to a defatting (lipid-removing) partition with a nonpolar solvent like hexane or petroleum ether, and then partition the residue between a semipolar organic solvent, such as chloroform or dichloromethane, and a polar aqueous solvent. A peculiarity of working on plant extracts is the need to remove a class of compounds known as “vegetable tannins” or “plant polyphenols” before subsequent biologic evaluation because these compounds act as interfering substances in enzyme inhibition assays, as a result of precipitating proteins in a nonspecific manner. Caution also needs to be expressed in regard to common saturated and unsaturated fatty acids that might be present in natural product extracts, because these may interfere with various enzyme inhibition and receptor binding assays.

Preparation of Initial Extracts and Preliminary Biologic Screening HTS: high-throughput screening Drug discovery from organisms is a “biology-driven” process, and as such, biologic activity evaluation is at the heart of the drug discovery process from crude extracts prepared from organisms. So-called high-throughput screening (HTS) assays have become widely used for affording new leads. In this process, large numbers of crude extracts from organisms can be simultaneously evaluated in a cell-based or non-cell-based format, usually using multiwell microtiter plates. Cell-based in vitro bioassays allow for a considerable degree of biologic relevance, and manipulation may take place so that a selected cell line may involve a genetically altered organism or incorporate a reporter gene. Innoncellular (cell-free) assays, natural products extracts and their purified constituents may be investigated for their effects on enzyme activity or on receptor binding. For maximum efficiency and speed, HTS may be automated through the use of robotics and may be rendered as a more effective process through miniaturization.

Methods for Compound Purification and Structure Elucidation and Identification Bioassay-directed fractionation is the process of isolating pure active constituents from some type of biomass (e.g., plants, microbes, marine invertebrates) using a decision tree that is dictated solely by bioactivity. Recent improvements have been made in column technology, automation of high-performance liquid chromatography (HPLC; a technique often used for final compound purification), and compatibility with HTS methodology. Routine structure elucidation is performed using combinations of spectroscopic procedures, with particular emphasis on 1H- and 13C-nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS).

Compound Development A major challenge in the overall natural products drug discovery process is to obtain larger amounts of a biologically active compound of interest for additional laboratory investigation and potential preclinical development. One strategy that can be adopted when a plant-derived active compound is of interest is to obtain a recollection of the species of origin. To maximize the likelihood that the recollected sample will contain the bioactive compound of previous interest, the plant recollection should be carried out in the same location as the initial collection, on the same plant part, at the same time of the year.

Compound Development Once a bioactive natural product lead is obtained in gram quantities, it is treated in the same manner as a synthetic drug lead and is thus subjected to pharmaceutical development, leading to preclinical and clinical trials. This includes lead optimization via medicinal chemistry, combinatorial chemistry, and computational chemistry, as well as formulation, pharmacokinetics, and drug metabolism studies, as described elsewhere in this volume. Often, a lead natural product is obtained from its organism of origin along with several naturally occurring structural analogs, permitting a preliminary structure–activity relationship study to be conducted.