chem 5300 final

• Goal of lead discovery process

  to find compounds that show activity (may be modest at first) in biological screens
• what are "hits"

  Compounds showing activity beyond a pre-determined threshold
• What is desirable hit range

  0.1-10%, depending on the drug target and class
• how are hits further tested

  Hits are further tested for their ability to cross membranes, cytotoxicity, and metabolism profile
• what are "leads"

  hits that pass further testing
• how to increase activity of a lead

  -structural modifications

  -Link between modification of a lead’s structure and changes in activity is called a structure-activity relationship (SAR)
• lead becomes a "candidate" when

  a lead has been adequately optimized and shows the desirable properties
• testing of candidates

  Tested in animals (efficacy and safety)
• what patent holder may legally do when compound is patent protected

  may legally exclude other from using that compound for the lifetime of the patent
• lifetime of a patent

  Finite lifetime: 20 years from date of filing in most jurisdictions
• what stage are patents typically filed in

  Patents are generally filed early in the lead optimization stage
• how long for typical drug candidate to reach market

  Typical drug candidate takes 7+ years to reach the market
• pros and cons of choosing when to file patent

  -Filing a patent too early leaves little of the 20-year window for profit on the drug

  -filing a patent too late increases risk of a competitor filing a patent on the same idea
• Before a drug can be tested on humans

  it must be tested on animals
• studies in humans are called

  clinical trials
• studies that occur prior to clinical trials are called

  preclinical trials or studies
• The two main types of preclinical testing

  -preclinical studies

  -preclinical trials
• preclinical studies

  Studies that are part of lead optimization
• preclinical trials

  Studies that are are standardized, industry-wide tests
• what does each preclinical trial seek to answer

  -safety questions of drug candidate

  -does not address therapeutic effectiveness
• animals involved in preclinical trials

  mice, rats, dogs, rabbits, and monkeys
• what animals preclinical trials must test before moving onto human testing

  Tests must involve at least one rodent and one non-rodent; goal is to determine whether the drug is safe to test in humans
• what are the tests on at least one rodent and one non rodent intended to reveal

  These are toxicology tests intended to reveal short-term (acute) side-effects, and animals must be given enough of the drug to demonstrate toxic effects
• why are subjects in early clinical trials almost always male

  Reproductive studies on pregnant rats and rabbits are normally not complete when the drug is first tested on humans
• process chemists role

  -To prepare large amounts of the candidate, the synthetic route may be modified from route used by the medicinal chemist team

  -Having an efficient, reproducible route for preparing the candidate in high purity is vital for the FDA approval process

  -Lead optimization may have required only gram quantities for testing, but animal studies may call for a kilogram or more
• Before a drug candidate can be tested in humans in the US

  an investigational new drug (IND) application must be filed with the Center for Drug Evaluation and Research (CDER) branch of the FDA
• what does IND application contain

  -a full summary of in-house screening, animal trials, and information on the synthetic route for preparing the compound

  -the company must also meet with representatives of the FDA to discuss their preclinical data
• IND candidates often called

  new chemical entities (NCE) or new molecular entities (NME)
• what happens after IND application approved by FDA

  If the drug seems safe and has promise of being effective, phase trials begin
• what are phase trials

  same thing as clinical trials and they occur in up to four phases that take place in sequence (I-IV)
• how may full phase trials be shortened or avoided

  If a company is seeking approval for use of drug in the US that has already been approved in another country, extensive data on human trials may already be available
• purpose phase 1 clinical trials

  -First introduction of investigational new drug (IND) into humans

  -Purpose of the Phase I clinical trial is to determine SAFETY and tolerance of the drug

  -NOT EFFECTIVENESS
• subjects of phase 1

  generally healthy volunteers (20-80 people) who are usually paid for their assistance
• How Subjects Monitored Phase 1

  -monitored for adverse side effects with increasing doses of the drug

  -Blood levels are monitored to determine properties such as half-life and metabolism of the drug
• what must phase 1 show before proceeding to phase 2

  Phase I trials must establish that the drug is safe (regarding acute, short-term side-effects) before Phase II trials can begin
• phase 1 drug disaster

  -in 2006 a Phase I study of TGN1412

  -Within 16 hours, all 6 patients were admitted to an intensive care unit with problems in their kidneys, heart, and lungs; all patients eventually recovered but may suffer long-term difficulties
• TGN1412

  -Pre-clinical safety testing failed to predict the adverse effects in humans

  -Incident highlights true experimental nature of clinical trials

  -adverse reactions were attributed to biological response pathways that could not be observed in the animal trials
• how phase 2 differs from phase 1

  -often the first time the drug is used on diseased patients

  -determine EFFECTIVENESS of drug as well as proper dosing
• phase 2 trials involve

  several hundred patients, and the cost per patient has been estimated to be about $25,000 US
• towards end of a phase 2 trial

  sponsoring company often meets with the FDA to present clinical and late animal data collected, and plans to move forward into Phase III trials are discussed