No idea on the target of the compound Expensive

the higher the affinity of a compound to receptor the stronger and more stable their bonding

Organic medicinal chemistry

In organic medicinal chemistry, we combine expertise from chemistry and biology to:

medicinal chemistry

basic understanding on medical principles, develop drug for diseases occurring in the community, significance in society skills and knowledge needed: 1- Chemistry 2- Biochemistry 3- Molecular Biology 4- Physiology 5- Pharmacology 6- Pharmaceutics 7- Medicine

drug formulation, design appropriate formulation of drug skills and knowledge needed: 1- Chemistry 2- Biochemistry 3- Molecular Biology 4- Physiology 5- Pharmacology 6- Pharmaceutics 7- Medicine

to optimize and modify the chemical structure of the drug to be more potent, enhance the effectiveness of the drug, and minimize the side effects skills and knowledge needed: 1- Chemistry 2- Biochemistry 3- Molecular Biology 4- Physiology 5- Pharmacology 6- Pharmaceutics 7- Medicine

understand normal process of the body to design a drug that is more effective with lesser side effects, understand pharmacokinetic processes skills and knowledge needed: 1- Chemistry 2- Biochemistry 3- Molecular Biology 4- Physiology 5- Pharmacology 6- Pharmaceutics 7- Medicine

identify potential biological targets, bind to specific enzyme skills and knowledge needed: 1- Chemistry 2- Biochemistry 3- Molecular Biology 4- Physiology 5- Pharmacology 6- Pharmaceutics 7- Medicine

biochemical process of living organisms to design compounds that would specifically target receptors and enzymes associated with a particular specie skills and knowledge needed: 1- Chemistry 2- Biochemistry 3- Molecular Biology 4- Physiology 5- Pharmacology 6- Pharmaceutics 7- Medicine

chemical structure, nomenclature, reaction, synthesis skills and knowledge needed: 1- Chemistry 2- Biochemistry 3- Molecular Biology 4- Physiology 5- Pharmacology 6- Pharmaceutics 7- Medicine

hypertension, if you know that angiotensin enzyme is associated with an increase in bp, you can design a drug that would target the angiotensin-converting enzyme skills and knowledge needed: 1- Chemistry 2- Biochemistry 3- Molecular Biology 4- Physiology 5- Pharmacology 6- Pharmaceutics 7- Medicine

field of science that manipulates living organism, cells, to create products

Cell – stimulating factors

Humanized monoclonal antibodies

Allows convenient production of insulin with lesser allergic reaction Inject insulin genes on microorganism (E. coli) to produce high yield of insulin

CONSIDERATIONS IN UNDERSTANDING THE PRINCEIPLES OF MEDICINAL CHEMISTRY EXCEPT:

It is important to consider the physicochemical properties of a drug in order to influence the absorption of the drug, distribution, metabolism, and even the pharmacologic response.

If the drug has activity on a particular enzyme, the receptor or enzyme to be targeted is known which would help determine the disease to be managed as well

Idea on metabolic product if it may cause toxicity or easily metabolized giving an idea on duration of action Phase of metabolism and potential toxic effects and side effects of metabolites to easily optimize it e.g., easily metabolized at low pH (optimize to an enteric coating)

Different enantiomers have different effects (Thalidomide R and S) one enantiomer has teratogenic effect which causes phocomelia while the other enantiomer has no teratogenic effect (remove 1 enantiomer to make it safer)

Spatial arrangement of atoms in a molecule

Racemic compound is a mixture of 3 enantiomer

PHYSICOCHEMICAL PROPERTIES OF LEAD COMPOUNDS CAN PROVIDE NEW DRUGS

The first histamine 2 antagonist developed

Histamine 2 is responsible for the production of gastric acid. If the receptor is stimulated, it would produce gastric acid. Through this, they developed a compound similar to histamine 2, They modified it to antagonize or inhibit histamine 2 receptors.

Ranitidine is derived from Cimetidine which is prone to side effects and various ADRs.

Generally, medicinal chemists can except:

Medicinal chemistry is devoted to the discovery and development of new agents for treating diseases Goal is to discover new therapeutic agent regardless of if it is organic or inorganic as long as it is effective

receptors

Receptors a relatively small region of a macromolecule which may be an/a:

_ are protein that interacts with a ligand to elicit pharmacologic response _ interacts with a substrate to catalyze a chemical reaction (speeds up the biochemical reaction)

Affinity

Intrinsic activity

Ability of a drug to exert a pharmacologic action

Compound binds to receptor and stimulates the effect or receptor to produce a pharmacologic effect

• Drug with affinity and intrinsic activity • Increases therapeutic response • Elicit pharmacologic response

• Drug with affinity but does not have intrinsic activity • Block the activity of the receptor • Does not elicit pharmacologic response

The response of a compound would depend on the presence of full agonist. If full agonist is present compound will act as antagonist. If full antagonist is absent the compound will act as agonist

Morphine _ to opiod receptor

Naloxone _ opiod receptor

Buprenorphine

In the presence of a full agonist, a compound acts as an antagonist as they compete on the same receptor. If there is a presence of a full agonist, the compound will become antagonist where if it binds to the receptor, it will block the activity and would not elicit a response In the absence of full antagonist, it will act as an agonist. It will stimulate the receptor producing a therapeutic response

In the presence of antagonist, its effect is agonist, in the absence of an antagonist its effect is agonist The response of a compound is dependent on the presence of a full agonist

Pure organic compounds are the chief source of agents for the cure, mitigation, or the prevention of diseas

Derived from plants, animals, microorganisms, fungi, bacteria

Synthetically made in the laboratory using chemicals (compounds made in lab using chemicals)

Other things that would affect the pharmocologic activity of the drug are physicochemical properties, solubility, pH, pharmacokinetic properties. it is better to categorize drugs through indication such as inflammatory, analgesic, anti-hypertensive

Drugs that act on the various physiological functions of the body (e.g., pain reliever , anti-inflammatory agents, general anesthetic, hypnotic and sedatives, analgesic etc.)

drugs which are used to fight pathogens, bacteria, virus, cancer cells, fungi (e.g., sulfonamides, antibiotics, anti-malarial agents, antiviral, anticancer, etc.)

Diseases that can be transmitted from one person to another Diseases that cannot be transmitted from person to person not caused by pathological state but rather a normal aspect of life

Disorders of the human body caused by generic malfunction, environmental factors, stress, old age, etc.

No changes in the body normal response e.g pain, contraception, drugs that are used as anesthetic agent Alleviation of pain (analgesic), prevention of pregnancy (contraception), anesthesia

Infectious disease and its causative agent? Pneumonia – Salmonella – Thrush –

Athlete's foot

Malaria

Amantadine is used Parkinsons but it was originally used in influenza. Later on, they found out that amantadine has an activity against Parkinsons disease.

Logical test Has knowledge or idea (you have prior knowledge) Systematic development based on the understanding about MOA or biological target

With enzyme linked assays or receptors from gene cloning of existing drugs lead to identification of new lead drug E.g., Amantadine

• X-ray crystallography • Nuclear magnetic resonance Evaluate the structure of the compound and design the compound in a way that it would interact with the target

HIV protease inhibitor

cimetidine

aliskerin

you are using living organisms you can optimize them or manipulate them to produce useful products. The two most commonly use are recombinant dna and mutagenesis

Induce changes in the DNA sequence Induce mutation in DNA In DNA sequence, pick specific location where the mutation willhappen

you are manipulating DNA or genetic material e.g insulin. The genes involved in the production of certain proteins Is inserted to a host

insulin and e coli

opium, belladona, ephedrine

insulin and thyroid

Penicillium notatum (Penicillin)

streptomycin and erythromycin

KCl and lithium

barbiturates, sulfonamides, ass

Crude plant drugs as opium, belladonna, and ephedrine that have been important for centuries

Accidental discovery of Penicillin gave birth to a large variety of antibiotics Random sampling of higher plants based on anecdotal

nontraditional or alternative medicinal

an antiviral agent protects and treats early influenza A • Treats parkinsonian disorders

utilizing the cell culture systems with linked enzyme assays and receptor molecules derived from gene cloning

Screen enormous libraries of peptides and nucleic acids obtained from procedures

ADVANCES IN RATIONAL DRUG DESIGN except:

Usually applied to compounds of known composition using the Chemical Abstract Services (CAS index)

Substance of plant or animal origin that cannot be classified as pure chemical compounds

Developed by the manufacturer; selected for their ease of recall but does not give a scientific information about the drug

A single, simple, informative designation available for unrestricted public use. Specific for a given compound even though it may possess a stem common to a related group of drug

Inhibited in a petri dish by the mold Penicillium notatum (Penicillin)

Took one step further by injecting Penicillium notatum on a live mice, with controlled experimentation, they found it cured mice with bacterial infections

Long process () to support that the lead compound is safe and effective before to be tested in human subjects

Clinical trial would take a decade. Drug discovery usually start with target selection.

The biological target should be druggable

CNS diseases must have a drug that can pass throught the blood brain barrier and it is very difficult to develop a drug that can easily penetrate the blood brain barrier. Thus, the target is _.

Once the biological target is identified, the next thing to do is to determine the lead compound. Lead compounds means has a potential to become a drug.

lead compound must have a good interaction with the biological target to prove that this compound can interact with the target.

cell lines, cytotoxicity assays

rats, any animals

In vitro – outside living organisms In vivo – conducted on living organisms

Drug discovery

synthesis & Isolation Combinatorial chemistry Assay development High throughput screening

Drug affinity & selectivity Cellular disease models MOA Lead candidate refinement

Animal models of disease states Behavioral studies Functional imaging Ex vivo studies