natural products and drug discovery - suli-pharma.com 2 building blocks oct 17... · pharmacognosy...

Natural Products and Drug Discovery

Pharmacognosy I – Third Lecture 2- NPs & Drug Discovery

Natural products definition…

Phytochemicals…

Building blocks…

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Secondary metabolism:

Biochemical reactions derived from primary metabolic

pathways used by plants, microorganisms, algae, marine

organisms, insects and some animals to accommodate

with their environment and/or growth regulation

through production of chemicals called secondary

metabolites.


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These metabolites show biological importance and are

targets for pharmaceutical industry.


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It is the study of the biochemical pathways leading to

the formation of secondary constituents that are used

as drugs.

The different types of biochemical reactions within the biologic

system will lead to sequence of different types of secondary

constituents used as drugs (Fig bellow)


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Enzymes and enzymatic reactions involved in the

construction of NPs.

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- Aldol and Claisen reactions…

Is a C-C bond formation in base catalyzed chemical

reaction through a resonance-stabilized enolate anion.

The starting material will be Coenzyme esters such as

AcetylCoA.

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- Mannich condensation Reaction…

Here we have the formation of C-N bond through

condensation between and aldehyde/Ketone and an

amine.

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- β-oxidation of fatty acids…

Is a catabolic degradation of fatty acids and

consequent release of (2C) acetyl-CoA in each step

catalyzed by multi-step enzymatic reaction…

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- Transamination reactions…

Is an exchange of the amine gp. In an amino acid

with a ketoacyl gp. Catalyzed by transaminases.

Homework// What is the co-enzyme in this reaction? And how it works.

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The glutamic acid–2-oxoglutaric acid couple provides

the usual donor–acceptor molecules


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- Decarboxylation reaction…

A degradative reaction ends with the removal of a

carbonyl gp. From an amino acid catalyzed by

decarboxylases.


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- Other reactions like oxidation-reduction and

oxidative coupling reactions also take place catalyzed

by oxidases and reductases.


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- Glycosylation reactions…

Addition of a sugar molecule (mostly D-Glucose) to

an aglycone moiety catalyzed by glycosidases. The

product is a glycoside. (the detailed reaction will be studied with

glycosides)


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Oxidative degradation of D-Glucose (glycolysis) and

formation of building blocks…


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Natural Products classes…

NPs are classified according to their chemical nature as

follows:-


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• Glycosides.

• Terpenoids.

• Steroids.

• Tannins.

• Phenylpropanoids.

• Lignans.

• Alkaloids.

• Peptides and Proteins.

• Carbohydrates.

• Fatty acids and eicosanoids.


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Drug development follows a logical progression from an

unmodified natural product (usually extracted from an herb) to a

synthetic modification of that natural chemical entity, to a purely

synthetic compound apparently showing little relationship to its

natural forebears.

The origin of drugs


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From viewing this structure, it composed

of a benzene ring and a side chain with a

terminal carboxyl group.

Same features are found in ASA, long

used for the same therapeutic effects as

ibuprofen.


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ASA does not occur in plants nor was it the original NSAID. That

recognition goes to Salicin (salicyl alcohol glycoside) that was first

isolated from the bark of the willow tree (Salix spp.) by the French

pharmacist H. Leroux in 1829.


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The first modern reference to the use of willow bark in treating

feverish conditions dates from 1763; however, both Hippocrates

and Celsus were familiar with the virtues of this plant.

After its isolation, salicin was shown to be a pro-drug that was

converted to the active principle, salicylic acid, in the intestinal

tract and liver following consumption.


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Meantime, salicylic acid had itself been isolated from other

sources, including meadowsweet, then known as Spiraea ulmaria

L. [now properly referred to as Filipendula ulmaria (L.) Maxim].

Because of this origin it was named spirsaure in German, or spiric

acid in English.


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Salicylic acid was found to possess excellent anti-inflammatory,

analgesic, and antipyretic properties, but even its sodium salt was

difficult to consume for lengthy periods because of the irritation

and damage it produced to oral mucosa, esophagus, and

particularly the stomach.


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After all, salicylic acid is an essential ingredient in corn

and wart removers and treatment of epidermis lesions

because of its keratolytic effects.


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Then, prior to 1899, a named Felix Hoffman at the Bayer Co. in

Germany took from the shelf a bottle of acetylsalicylic acid and

administered a quantity of it to his rheumatic father who could

no longer take sodium salicylate. It proved to be both effective

and well tolerated.

Thus, ASA (acetyl spiric acid) was introduced into medicine.


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Over the years, numerous modifications of the salicylic acid

molecule have been made synthetically in attempts to improve its

action and reduce its side effects. Acetanilide proved too toxic;

phenacetin was carcinogenic;


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Acetaminophen is used as an analgesic but lacks anti-

inflammatory properties; and the newer NSAIDs, such as

ibuprofen, all have advantages and disadvantages but are

generally quite effective.


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All these previous agents share similar stereochmical

features that seems to be essential for their

pharmacological actions including:-


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1. A flat configuration enabling them to fit a specific receptor

site on an enzyme.

2. Acidic and strongly ionized at a physiological pH allowing

aqueous solubility to concentrate in plasma and extracellular

water.

3. Sufficient lipid solubility to allow them to penetrate biological

membranes easily.


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Developing a new drug from original idea to the launch of

a finished product is a complex process which can take 12-

15 years and cost in excess of $1 billion in many cases.


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Stages of Drug Development

1.Discovery

2.Product Characterization

3.Formulation, Delivery, Packaging Development

4.Pharmacokinetics And Drug Disposition

5.Preclinical Toxicology Testing

6.Bioanalytical Testing

7.Clinical Trials


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The idea for a target can come from a variety of sources including

academic and clinical research and from the commercial sector.

It may take many years to build up a body of supporting evidence

before selecting a target for a costly drug discovery programme.


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Once a target has been chosen, the pharmaceutical industry and

more recently some academic centers have streamlined a

number of early processes to identify molecules which possess

suitable characteristics to make acceptable drugs.


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The following review will look at key preclinical stages of the drug

discovery process, from initial target identification and validation,

through assay development, high throughput screening, hit

identification, lead optimization and finally the selection of a

candidate molecule for clinical development.


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Lead molecules oftenly comes from natural sources


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Discovery often begins with target identification choosing a

biochemical mechanism involved in a disease condition.

Drug candidates, discovered in academic and

pharmaceutical/biotech research labs, are tested for their

interaction with the drug target.


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Up to 5,000 to 10,000 molecules for each potential drug candidate

are subjected to a rigorous screening process which can include

functional genomics and/or proteomics as well as other screening

methods.


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Once scientists confirm interaction with the drug target, they

typically validate that target by checking for activity versus the

disease condition for which the drug is being developed.

After careful review, one or more lead compounds are chosen.


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When the candidate molecule shows promise as a therapeutic

agent, it must be characterized—the molecule’s size, shape,

strengths and weaknesses, preferred conditions for maintaining

function, toxicity, bioactivity, and bioavailability must be

determined.


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Early stage pharmacology studies help to characterize the

underlying mechanism of action of the compound.


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Drug developers must devise a formulation that ensures

the proper drug delivery parameters.

It is critical to begin looking ahead to clinical trials at this

phase of the drug development process.


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Drug formulation and delivery may be refined continuously until,

and even after, the drug’s final approval.

Scientists determine the drug’s stability in the formulation itself,

and for all the parameters involved with storage and shipment,

such as heat, light, and time.


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The formulation must remain active and sterile; and it

must also remain safe (nontoxic) during shelf live.


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Pharmacokinetic (PK) or ADME

(Absorption/Distribution/Metabolism/Elimination) studies provide

useful feedback for formulation scientists. PK studies yield

parameters such as AUC (area under the curve), Cmax (maximum

concentration of the drug in blood), and Tmax (time at which Cmax

is reached).


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Later on, this data from animal PK studies is compared to

data from early stage clinical trials to check the predictive

power of animal models.


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Preclinical Toxicology Testing and IND Application


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Preclinical testing analyzes the bioactivity, safety, and

efficacy of the formulated drug product.


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Testing is critical to a drug’s eventual success and, as such, is

scrutinized by many regulatory entities.

During the preclinical stage of the development process, plans for

clinical trials and an Investigative New Drug (IND) application are

prepared. Studies taking place during the preclinical stage should

be designed to support the clinical studies that will follow.


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The main stages of preclinical toxicology testing are:

Acute Studies

Acute toxicology studies look at the effects of one or more doses

administered over a period of up to 24 hours. The goal is to

determine toxic dose levels and observe clinical indications of

toxicity.


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Usually, at least two mammalian species are tested.

Data from acute toxicology studies helps to determine

doses for repeated dose studies in animals and Phase I

studies in humans.


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Repeated Dose Studies

Depending on the duration of the studies, repeated dose studies

may be referred to as subacute, subchronic, or chronic.

The specific duration should anticipate the length of the clinical

trial that will be conducted on the new drug. Again, two species

are typically required.


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Genetic Toxicity Studies

These studies assess the likelihood that the drug compound is

mutagenic or carcinogenic. Procedures such as the Ames test

(conducted in bacteria) detect genetic changes. DNA damage is

assessed in tests using mammalian cells such as the Mouse

Micronucleus Test. The Chromosomal Aberration Test and similar

procedures detect damage at the chromosomal level.


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Reproductive Toxicity Studies

Segment I reproductive toxicology studies look at the effects of

the drug on fertility. Segment II and III studies detect effects on

embryonic and post-natal development.

In general, reproductive toxicological studies must be completed

before a drug can be administered to women of child-bearing age.


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Carcinogenicity Studies

Carcinogenicity studies are usually needed only for drugs intended

for chronic or recurring conditions. They are time consuming and

expensive, and must be planned for early in the preclinical testing

process.


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Toxicokinetic Studies

These are typically similar in design to PK/ADME studies except

that they use much higher dose levels. They examine the effects of

toxic doses of the drug and help estimate the clinical margin of

safety. There are numerous FDA and ICH guidelines that give a

wealth of detail on the different types of preclinical toxicology

studies and the appropriate timing for them relative to IND and

NDA or BLA filings.

See Regulatory/Animal Welfare and at

www.fda.gov/cder/guidance/index.htm.


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Bioanalytical Testing


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Bioanalytical laboratory work supports most of the other activities

in the drug development process. The bioanalytical work is key to

proper characterization of the molecule, assay development,

developing optimal methods for cell culture or fermentation,

determining process yields, and providing quality assurance and

quality control for the entire development process.

It is also critical for supporting preclinical

toxicology/pharmacology testing and clinical trials.


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Clinical Trials


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Clinical studies are grouped according to their objective into three

types or phases:

Phase I Clinical Development (Human Pharmacology) - Thirty days

after a biopharmaceutical company has filed its IND, it may begin a

small-scale Phase I clinical trial unless the FDA places a hold on the

study. Phase I studies are used to evaluate pharmacokinetic

parameters and tolerance, generally in healthy volunteers. These

studies include initial single-dose studies, dose escalation and

short-term repeated-dose studies.


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Phase II Clinical Development (Therapeutic Exploratory) - Phase

II clinical studies are small-scale trials to evaluate a drug’s

preliminary efficacy and side-effect profile in 100 to 250 patients.

Additional safety and clinical pharmacology studies are also

included in this category.


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Phase III Clinical Development (Therapeutic

Confirmatory)

Phase III studies are large-scale clinical trials for safety

and efficacy in large patient populations.


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Phase III Clinical Development (Therapeutic Confirmatory)

While phase III studies are in progress, preparations are made for

submitting the Biologics License Application (BLA) or the New

Drug Application (NDA).

BLAs are currently reviewed by the FDA’s Center for Biologics

Evaluation and Research (CBER).

NDAs are reviewed by the Center for Drug Evaluation and

Research (CDER).


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Review of the lecture


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Thank You Any questions?


natural products and drug discovery - suli-pharma.com 2 building blocks oct 17... · pharmacognosy...

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