DRUG DISCOVERY AND DRUG PRODUCT - A popular term for a generic drug with an

identical formulation and stated indications as

DEVELOPMENT
a drug previously approved by the FDA.
DRUG DEVELOPMENT BEFORE Me-too drugs
 Even before the synthetic, target-based, and - Pharmacologically active compound that is
selective medicinal agents, remedies were structurally related to a first-in-class
abundantly provided by various plant sources compound, regarded as belonging to the same
more commonly referred to as herbal remedies. therapeutic class as the original compound,
Dating back to the cavemen following their and used for the same therapeutic purposes,
instincts to survive or preserve their lives, drugs but which may differ in some respects, such as
already exist in various forms. specificity of pharmacological action, adverse
reactions profile, or drug-drug interactions.
NEW DRUG DEVELOPMENT PROCESS
4. Combinatorial synthesis
Discovery Phase - includes synthesis, isolation, 5. Computer-aided design
fermentation, screening, and SAR studies.
6. Serendipity and prepared mind
1. Choosing a disease — the focus is on the financial 7. Use of NMR
return.
8. High Throughput Screening
2. Choosing a drug target — receptor, enzymes, and
nucleic acid. - Large libraries of compounds are tested for
- Depend on finding the drug first. their ability to modify the target.
- discovery of the chemical messenger. - Capable of examining 15,000 chemical
- Genome projects — an increasing number of compounds a week using 10 — 20 bioassays.
new receptors and enzymes — potential drug
targets. “Over the past two decades [the drug industry] has moved
- a key molecule that is involved in a particular very far from its original high purpose of discovering and
metabolic or signaling pathway that is specific producing useful new drugs.”
to disease.

3. Identifying a bioassay In her 2004 expose, “The Truth About the Drug Companies:
How They Deceive Us and What to Do About It,” Dr. Marcia
- In vivo test — inducing a clinical condition and Angell, former editor-in-chief of The New England Journal
treating it with the test drug. of Medicine, points out that pharmaceuticals are the fastest
- In vitro test — drug activity is tested on rising segment of our national healthcare bill—and yet 75
isolated tissues, cells, or enzymes. percent of all new drugs coming off to market are merely
imitations of existing medications.
4. Finding a Lead Compound
Tagamet Prilosec
- A compound showing a desired
pharmacological property that can be used to Zantac Nexium
initiate a medicinal chemistry project.
- Ways of discovering a lead compound
5. Isolate and purify the lead compound.
WAYS OF DISCOVERING A LEAD COMPOUND
6. Determine the structure — NMR, IR
 Screening of natural products spectroscopy, X-ray crystallography, LC-MS.
 Plant kingdom — morphine, cocaine, quinine, 7. Identify the structure-activity relationship — in
periwinkle (vincristine and vinblastine), reserpine, vitro.
paclitaxel.
 Microbiological world — penicillin, cephalosporin, 8. Identify the pharmacophore (atoms and
tetracyclines, aminoglycosides, lovastatin. functional groups required for a specific
 Animal sources - proteins (somatostatin, pharmacological activity, and their relative
glucagon,) polysaccharides (heparin) bile acids, positions in space).
estrogens (urine of pregnant mare). 9. Improve target interaction and pharmacokinetic
 Biological source — vaccines (living or killed properties.
microorganisms). 10. Study drug metabolism and test for toxicity.
1. Medical folklore 11. Design a manufacturing process.
2. Screening synthetic banks PRE-CLINICAL TRIALS
3. Existing drugs (me too drugs)
 Phase which includes:
 - Chemical and physical characterization,  Filed before the drug may be given to humans
pharmacology, pharmacokinetics, (clinical trials).
pharmacodynamics, pharmaceutics, analytical  Special consideration is given to Orphan drugs
studies, toxicology (treatment IND).
 Pharmacology — the science of the properties of  orphan drug is used to treat orphan disease, or
the drugs and their effects in the body. disease that affects fewer than 200,000 people in
 Pharmacodynamics — the study of the interaction the US.
of drugs with cells.  Submitted to FDA > Review by FDA for 30 days.
 Pharmacokinetics — the handling of a drug within
the body, it includes the ADME processes.
 Toxicity testing — in vitro and in vivo testing, 12.CARRY OUT THE CLINICAL TRIAL
determination of LD 50.
 Pharmaceutics — the general area of study PHAS NO. OF PURPOSE %
concerned with the formulation, manufacturing, E PATIENT SUCCESSFULL
stability, and effectiveness of a pharmaceutical S Y
dosage form. COMPLETING
I 20-80 Healthy Safety 67
UNDER FDA REQUIREMENTS volunteer
s
A sponsor must first submit data showing that the drug is
II 100-300 Suffer Safety and 45
reasonably safe for use in initial, small-scale clinical studies.
from the effectivenes
Depending on whether the compound has been studied or target s
marketed previously, the sponsor may have several options illness
for fulfilling this requirement:
III 1000- With the Safety, 5-10
 (1) compiling existing nonclinical data from 3000 target effectivenes
illness s, and
past in vitro laboratory or animal studies on
dosage
the compound.
 (2) compiling data from previous clinical
testing or marketing of the drug in the United
States or another country whose population is
relevant to the U.S. population.
 (3) undertaking new preclinical studies
designed to provide the evidence necessary to
support the safety of administering the
compound to humans.

DURING PRECLINICAL DEVELOPMENT... Phase I

 A sponsor evaluates the drug's toxic and  These studies are designed to determine the
pharmacologic effects through in vitro and in vivo metabolic and pharmacological actions of the
laboratory animal testing. drug in humans, the side effects associated with
 Genotoxicity screening is performed, as well as increasing doses, and, if possible, to gain early
investigations on drug absorption and metabolism, evidence of effectiveness.
the toxicity of the drug's metabolites, and the  These studies also evaluate drug metabolism,
speed with which the drug and its metabolites are structure-activity relationships, and the
excreted from the body. mechanism of action in humans.
 Studies usually test new drugs for the first time
At the preclinical stage, the FDA will generally ask, at a
in a small group of people to evaluate a safe
minimum, that sponsors
dosage range and identify side effects.
- Develop a pharmacological profile of the drug.
Phase 2
- Determine the acute toxicity of the drug in at
least two species of animals.  This phase of testing also helps determine the
- Conduct short-term toxicity studies ranging common short-term side effects and risks
from 2 weeks to 3 months, depending on the associated with the drug.
proposed duration of use of the substance in  Failure during Phase II testing is common.
the proposed clinical studies.  After phase 2, sponsors meet with FDA.
 Studies test treatments that have been found to
FILE IND APPLICATION
be safe in Phase I but now need a larger group
Investigational New Drug Application of human subjects to monitor for any adverse
effects.
Phase 3 ACIDS

 These studies are intended to gather the

additional information about effectiveness and
safety that is needed to evaluate the overall
benefit-risk relationship of the drug.
 These studies also provide an adequate basis for
extrapolating the results to the general population BASES
and transmitting that information in the physician
labeling. - A base which ionizes almost completely in
 Studies are conducted on larger populations and solution is said to be a strong base, whereas
in different regions and countries and are often one which has a small degree of ionization is a
the step right before a new treatment is weak base.
approved.
3. LEWIS THEORY
14. Market the Drug

Phase 4

 Post-marketing studies and manufacturing scale-

up activities take place ¢Modification on drug
formulation as obtained from manufacturing scale- ACID STRENGTH  refers to its ability or tendency to
up and validation process may be done. lose a proton (Hᶧ).
 Studies take place after country approval and
there is a need for further testing in a wide Acid dissociation Constant (Kₐ)  measures the strength of
population over a longer timeframe. an acidic molecule.
NEW DRUG APPLICATION pH  Measures the strength of an aqueous acid solution.

 Submission of New Drug Application (NDA)

STRONG completely ionizes HCI, HI, HBr,
 NDA is submitted for review and approval after the
ACID (dissociates) in a HCIO, HNO₃,
completion of the clinical trials and requirements
solution H₂SO₄
have been met.
 Give permission to market drug product. WEAK ACID partially dissociates H₂CO₂
 ANDA — Abbreviated NDA - Generic drug CH₃COOH
ACID-DISSOCIATION EQUATION

Ionization Constant (Ka)

- It indicates the relative strength of the acid or

base.

An acid with a Ka of I x 10¯¹ is stronger (more ionized)

than one with a Ka of I x 10¯³.
PHYSICOCHEMICAL PROPERTIES
 where a base with a Ka of I x 10¯⁷ is weaker (less
ACID- BASE PROPERTIES ionized) than one with a Ka of I x 10¯⁹.

2. Acid dissociation Constant expression, (Kₐ).

K ₐ=( H ᶧ ) ¿ ¿
Negative log of the ionization constant

 (pKa)
2. ARRHENIUS THEORY
  An acid with a pKa of 5 (Ka = I x 10¯⁵) is weaker Drug Polarity
(less ionized) than one with a pKa of 3 (Ka = I x
10¯³), - It is a relative measure of a drug's lipid and
 whereas a base with a pKa of 9 (Ka = I x 10¯⁹) is water solubility and is usually expressed in
stronger (more ionized) than one with a pKa of 7 terms of a partition coefficient.
(Ka = I x 10¯⁷)
 Water solubility (or hydrophilicity) depends primarily
Ionization for acids and bases on two factors:

 Weakly acidic drugs are less ionized in acid media 1. Ionic character
than in alkaline media. When the pka of an acidic 2. Hydrogen-bonding capabilities
drug is greater than the pH of the medium in
The presence of oxygen and nitrogen-containing functional
which it exists, it will be more than 50% in its
groups usually enhances water solubility.
nonionized (molecular) form and thus, more likely
to cross lipid cellular membranes. Water solubility is required for:
Organic acids contain one or more of these functional  (1) Dissolution in the gastrointestinal (Gl) tract
groups:
 (2) Preparation of parenteral solutions (as opposed
to suspensions)
 (1) Carboxylic acid group (COOH)
 (3) Preparation of ophthalmic solutions
 (2) Phenolic group
 (4) Adequate urine concentrations (pertains
 (3) Sulfonic acid group
primarily to antibiotics)
 (4) Sulfonamide group
 (5) Imide group Lipid solubility (or lipophilicity) is enhanced by
 (6) beta-carbonyl group nonionizable hydrocarbon chains and ring systems.
Strong inorganic bases Lipid solubility is required for:
 sodium hydroxide  (1) Penetration through the lipid bilayer in the GI
 potassium hydroxide tract
 magnesium hydroxide  (2) Penetration through the blood brain barrier.
 calcium hydroxide  (3) Preparation of intramuscular (IM) depot
 barium hydroxide injectable formulations.
 and quaternary ammonium hydroxides
 are also completely ionized. Partition coefficient (P)

Organic bases contain the following functional groups:  defined as the ratio of the solubility of the
compound in an organic solvent to the solubility of
 (1) primary, secondary, or tertiary aliphatic or the same compound in an aqueous environment.
alicyclic amino group
 (2) most aromatic or unsaturated heterocyclic P = [Drug] lipid/[Drug]aqueous
nitrogen.
A. Acids and Bases OCTANOL LIPID
B. Solubility
- The amount in milliliters of water capable of WATER WATER
dissolving one gram of a given substance.
DRUGS IN SALT FORM
Some basic properties of water
 A salt is the combination of an acid and a base.
a. Bond angles  Two classes based on the chemical nature of the
substance:
--Inorganic Salts are made by combining drug
molecules with inorganic acids and bases
 Increased water solubility in comparison with
the parent molecule
b. Charge distribution
-- Organic salts are made by combining two drug
molecules, one acidic and one basic
 Increased lipid solubility; generally, is used to
make depot injections.

LIPINSKI'S RULE OF 5

c. H- bonding  Pfizer's rule of five or rule of five (ROS)

  Rule of thumb to evaluate drug-likeness or proportional to the number of receptors
determine if a chemical compound with a certain occupied by the drug.
pharmacological or biological activity has chemical  AFFINITY - measure of how strongly a drug binds
properties and physical properties that would
to a receptor.
make it a likely orally active drug in humans.
 No more than 5 hydrogen bond donors (the total  EFFICACY - maximum biological effect resulting
number of nitrogen— hydrogen, and oxygen— from a drug binding to its target.
hydrogen bonds).  ENZYME
 No more than 10 hydrogen bond acceptors (all - protein catalysts produced by living cells by
nitrogen or oxygen atoms). acting as a surface or focus for the reaction,
 A molecular mass of less than 500 Daltons. bringing the substrate(s) together and holding
 An octanol-water partition coefficient (log P) that
them in the best position for the reaction.
does not exceed 5.

---- Omeprazole is a popular drug that conforms to Lipinski’s

rule of 5.

PHARMACODYNAMIC
PHARMACODYNAMIC PHASE

 Drug actions  dynamic interactions between TYPES OF RECEPTOR ACTION

drug molecules and cellular components.  Down-Regulation
- caused by continuous prolonged exposure of
receptors to drugs that disrupt the
homeostatic equilibrium and result in altered
levels of the receptors.
- This disruption involves endocytosis of ligand-
bound receptors, resulting in:
Types of molecules that a drug may act upon:
 sequestration of receptors from the cell
 Lipid -- Amphotericin B surface
 Carbohydrate -- used as molecular tag.  accelerated degradation of the receptors,
 Protein -- receptors  or inactivation of the receptors.
 Nucleic acids -- DNA and RNA acting as drug
target.

RECEPTOR

 Cell or group of cells specialized to detect changes

in the environment and trigger impulses in the
sensory nervous system.
 protein in nature and embedded in the cell
membrane.
 Ligand - a molecule that binds to a receptor.
 Desensitization
Theories describing the pharmacologic activity of the drug:
- Result of down – regulation
 LOCK AND KEY THEORY - The target cells become desensitized and the
- completely complementary relationship effect of subsequent exposure to the same
between the drug molecule and a specific concentration of the drug is reduced.
area on the surface of the receptor molecule. - An increased concentration of the drug is
 INDUCED FIT THEORY required to produce an effect of the same
- complementary relationship between the drug magnitude as the initial exposure with a
molecule and its active site. smaller drug concentration.
 OCCUPATIONAL THEORY OF RESPONSE -
- the intensity of pharmacologic activity of a
structurally specific drug is directly