1. Drug Discovery &Development

2. Discovery of new drugs is very important to improve the quality of life and to manage chronic diseases.
The value of new drug depends on:
Its ability to reduce the mortality and morbidity.
Decrease social cost of disease.
Enhance social and economic progress.

3. The cost of drug development from discovery to official approval averages about 900 million dollars, and the time between the initial preclinical studies and marketing can range from 3.2 to 20 years.
Therefore, drug discovery and development is very complex, risky and expensive.

4. Steps of drug discovery and development

5. Drug Discovery & Development
Identify disease
Find a drug effective
against disease protein
(2-5 years)
Isolate protein
involved in
disease (2-5 years)
(Target selection)
Preclinical testing
(1-3 years)
Human clinical trials
(2-10 years)
File IND
Formulation
File NDA
FDA approval
(2-3 years)

6. Target selection:
Drug target usually proteins (receptors, enzymes, transport proteins) or other targets includes DNA.
New target identification depends largely on advanced knowledge of the pathophysiology of the disease, for example:
Inhibiting angiotensin converting enzyme lowers blood pressure by suppressing angiotensin formation
Further advance was the finding of angiotensin receptors and block them with angiotensin receptor blockers, further advance……………??.

7. Design and synthesis of active substances:
After identification of the target, now we must search for suitable compound that act on that specific target.
The sources of these compounds usually the followings:
Plants: digoxin, atropine.
Human cells: urokinase
Animal tissue: heparin
Gene technology: human insulin
Microbial culture: penicillin
Synthetic chemicals: piroxicam, ziprasidone

8. Millions of such compounds can be screened in short period of time by highly sophisticated electronic machines to find the compounds that can act on the specific target.

9. Some of the compounds that have been shown to be effective against the target, practically cannot be used as drugs because it have undesirable features such as:
high molecular weight, excessive polarity, possession of groups known to be associated with toxicity.
The chosen compounds now undergo optimization to increase their potency, selectivity, and metabolic stability by molecular modulation.

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11. Preclinical development:
The aim of preclinical studies to ensure safety and efficacy of the drug in isolated tissues or animals before administration to humans. These include the following:
Pharmacological studies:
Selectivity and mechanism of action of the drug
Pharmacokinetics: absorption, distribution, metabolism, and excretion.
Adverse effects: bronchoconstriction, cardiac arrhythmias, blood pressure changes and ataxia.

12. Toxicological studies:
To determine the maximum non-toxic dose of the drug (acute and chronic uses).
Mutagenicity: to identify compounds that can cause genetic damage.
Carcinogenicity: to identify compounds that can induce cancer, this usually required only if the drug is to be given to man for above one year or the compound resembles a known carcinogen, or it is mutagenic.
Reproductive studies:
To see the effects of the new compounds on fertility, fetal organogenesis, and peri- and postnatal development.

13. The clinical development process divided into 4 phases:
When the above preclinical (animal) studies prove to be successful, a license to be used in humans should be taken from an official agency.
The clinical development process divided into 4 phases:

14. Phase I: Usually involve small numbers of healthy volunteers (25-50)
Establish the dose-response curve of the new drug, find the maximum tolerated dose.
Check for safety (potential dangerous effects) and tolerability (symptoms).
Find out the pharmacokinetics properties of the drug.

15. Phase II: Performed on group of Patients (100-300).
This study designed to test for efficacy in clinical situation
Establish the dose to be used in the next phase.
These studies usually single-blind and the new drug compared with placebo.
Blinding: procedure done during clinical trials to keep the people involved in the trial (participant or investigator) unaware of the drug that is being given or evaluated.
Placebo: an inert substance, identical in all aspects to the active treatment, given as if it was a real treatment

16. Phase III:
The drug evaluated in large number of patients with the target disease ( ).
The aim is comparing the new drug with commonly used alternatives regarding efficacy and safety.
These studies usually double-blind.

17. Phase IV:
When the above 3 phases end with success, the drug now approved by official agency to be produced by pharmaceutical companies and marketed to the population.
After marketing, the drug surveillance continues for safety and toxicity in large number of patients.