Studied by 25 people
Germ theory of disease
Airborne infection was the underlying cause
Immunization procedures
Chemotherapy
"Vital staining"
Receptor and Magic bullet
Antitoxin and bacteria
Stupefying agent
Anesthetic
1st therapeutic drug to come from synthetic chemistry (Gunthrie, 1859)
Vasodilating effects (Brunton, 1864)
Precursor of mauvein
Accidental discovery by Perkin for supposedly Quinine, 1865
Became the established model in the early part of the 20th century
Key discipline in drug discovery; prevailed for 50 years ·
Research management was largely at hand of the chemists
Pharmaceutical companies on "love-hate" relationship
Pharmaceutical industry has difficulty in synthesizing structures.
Natural products remain significant source of drugs.
Concept of Chemotherapy
Paul Ehrlich is the first "modernist" who defined the principles of drug specificity in terms of specific interaction between a drug molecule and a target molecule.
"Corpora non agunt nisi fixata"
Chemistry remained empiric for many years.
"Magic bullet"
By Hitching and Elions in 1944
Interest in the synthesis of folic acid, purines and pyrimidines as chemotherapeutic agents
Identified dihydrofolate reductase which is necessary for DNA synthesis.
Pyrimidine analogues inhibited the enzyme
Emergent drugs include: Pyrimethamine, Trimethoprim, 6- mercaptopurine, Azathioprine, Aciclovir, Zidovudine
Drug antagonism
Classes of receptors have varied effects
System of "prescription only" medicines
What info should be on the label; system of "what cures"
Controlling of addictive substances
Thalidomide disaster
Chemie Grunenthal
UK began to follow US regulatory laws in safety; urgent reappraisal because of the incident
Etablishment of Commission on the Safety of Drugs o
All new drugs has to be submitted for approval before clinical trials and market release
Medicines Act (closed the loophole) - added efficacy
Anticoagulant
Synthetic compound from dicoumarol
Found in spoiled sweet clover
Anticoagulant
Occurring naturally in mammalian tissues
Anticoagulant from leech
Now produced by genetic engineering
Caffeine and Theophylline
Phosphodiesterase inhibitors and adenosine receptor antagonists
Produced by tea, coffee, coca plants
HMG CoA reductase inhibitors used to reduce plasma cholesterol
Lovastatin is a fungal metabolite
Later compounds (mevastatin, pravastatin) synthesized from lovastatin
Asthma prophylaxis
Synthetic compound based on khellin, plant for herbal medicine
Vincristine and Vinblastine
Anticancer drugs produced by plants of the periwinkle family
Antimalarial drug
Semisynthetic derivative of artemisinin, a chinese herb
Antihelminthic drug
Semisynthetic derivative of avermectin, a fungal metabolite
Too numerous to list
Majority of current antibiotics are derived from fungal metabolites
Gene mutations of which cause or predispose to the development of human disease.
Concept of "inborn errors of metabolism"
This class of disease genes does not seem to include many obvious drug targets.
These are non-mutated genes that are directly involved in the pathophysiological pathway leading to the disease phenotype.
The phenotype may be associated with over or underactivity of the gene product detectable by expression profiling.
This is the most important category in relation to drug targets as therapeutic drug action generally occurs by changing the activity of functional proteins, whether or not disease alters their expression level
Principle: development of any disease phenotype involves changes in gene expression in cells and tissues involved.
"Critical path genes" may represent potential drug targets, some are "bystander genes" How to identify using this method: group genes into functional classes, then determine plausibility criterion in causing a disease; identify genes which are co-regulated and might point to a biochemical signaling
For a gene product to serve as drug target, it must possess a recognition site capable of binding small molecules.
They likely to possess a binding site irrespective of whether such interaction will have a therapeutic value
It refers to the experimental approaches by which a potential drug target can be tested and given further credibility.
Main approaches are pharmacologic and genetic
Lack of efficacy causes abandonment of roughly 1/3 of drugs in Phase II, reflecting unreliability of the earlier evidence for target validity
