module 1

• Drugs are molecules used as medicines or as components in medicines to diagnose or treat disease.
• Drugs generally are not discovered directly; first a lead compound is identified.
• A lead compound is a prototype having desired activity but also other undesirable characteristics, such as toxicity, other activities, insolubility, metabolism problems, oral bioavailability.
• Lead compounds are modified by synthesis to amplify desired activity and to minimize or eliminate undesirable properties, producing a drug candidate (compound worthy of extensive biological, pharmacological, and animal testing).
• Medicinal Chemistry is the science that deals with the discovery or design of new potential therapeutic agents and their development into useful medicines.
• Medicines are substances used to treat diseases.
• Medicinal Chemistry Folklore suggests that the earliest medicines were discovered around 5,100 years ago by Chinese emperor Shen Nung in his book of herbs, Pen Ts’ao Ma Huang.
• The average time to bring a drug to market is 8-15 years.
• Guanylate cyclase stimulates the formation of cGMP, which in turn stimulates smooth muscle relaxation and increased blood flow.
• Foreign organisms and aberrant cell growth can lead to enzyme inhibition or DNA interaction.
• Dramamine and Zyban, which are also found to have side effects in clinical trials, are also known to inhibit phosphodiesterase 5.
• Rational Drug Discovery involves identifying targets through chemical imbalances, foreign organisms and aberrant cell growth.
• Prolongation of penile erections is a reported side effect of phosphodiesterase isozyme inhibition in the corpus cavernosum.
• For every 20,000 compounds evaluated in animals, only 10 make it to human clinical trials, and of those 1, only 1 goes to market.
• Quinpirol binds to the dopamine D 3 receptor in the intracellular domain.
• Proteins are polymer chains of amino acids that loop and fold to produce grooves, cavities, and clefts that are ideal sites for interaction with other molecules.
• Nonrandom or Targeted or Focused screening screens compounds related to active compounds.
• Quinpirol bound to dopamine D 3 receptor depicts the conformation when the drug is bound.
• Sources of lead compounds include the natural ligand for the target of interest, such as dopamine being the natural ligand for dopamine receptors, and another substance already known to interact with the target of interest, such as cytisine interacting with nicotinic acetylcholine receptors.
• Chemical imbalances can lead to either agonism or antagonism of a receptor or enzyme inhibition.
• The mechanism of action of Viagra involves the inhibition of phosphodiesterase 5, which leads to smooth muscle relaxation and increased blood flow.
• Rational approaches identify causes for disease states such as imbalance of chemicals in the body, invasion of foreign organisms, and aberrant cell growth.
• Lead discovery involves identifying biological systems involved in disease states, using a natural receptor ligand or enzyme substrate as the lead, and a known drug also can be used as a lead.
• Drug metabolism studies involve screening metabolites produced for the same or other activities.
• Clinical observations are a source of new activities found in clinical trials, for example, Dramamine was tested as an antihistamine and found to relieve motion sickness, and Viagra was tested as an antihypertensive and found to treat erectile dysfunction.
• Random screening is an approach before 1935 where all compounds are screened.
• Screening involves conducting a biological assay on a large collection of compounds to identify compounds that have the desired activity, initially these compounds may bind weakly to the target and are known as “hits”.
• A good lead molecule interacts with the target consistent with that needed to achieve the desired effect, is amenable to synthetic modifications needed to improve properties, and possesses, or can be modified to possess, physical properties consistent with its ability to reach the target after administration.
• Medicinal Chemistry Folklore also suggests that modern therapeutics include the Extract of foxglove plant, cited by Welsh physicians in 1250, used to treat dropsy (congestive heart failure) in 1785, and contains digitoxin and digoxin, today called digitalis.
• Genomics (identification of new gene targets) and proteomics (identification of proteins expressed) are new directions for drug discovery.
• Drug development is a long and expensive endeavor: it takes about 12 years for a drug to move from preclinical testing to final approval.
• The cost to get to market has increased over the years: 1962 - $4 million, 1996 - $350 million, 2002 - $600 - $800 million, 2013 - $1.2 - 1.8 billion.
• A generic drug should have the same active ingredients, the same amount, the same quality, the same safety and efficacy of the brand-name drug.
• Only ~6000 known drugs of the estimated 10^60 possible compounds are known.
• Phase IV studies may reveal new indications for a drug with patients having symptoms from other diseases.
• A generic drug becomes available 20 years after the patent on the brand-name drug expires.
• For every 20,000 compounds tested in animals, 10 go to clinical trials, and 1 goes to market.
• A generic drug is equivalent to the brand-name drug.
• It is estimated that it costs approximately $1 - 3 billions to develop a new drug, taking into account the high failure rate, wherein only 10 – 20% of drugs tested are successful and reach the market.
• Once the drug is on the market, its safety and tolerability can be assessed because it is taken by hundreds of thousands, if not millions, of people, referred to as Phase IV studies.