Sources of new drugs Flashcards
what is lead discovery
the process of identifying active new chemical entities, which by subsequent modification may be transformed into a clinically useful drug
what is lead generation
strategies developed to identify compounds which possess a desired but non optimised biological activity
what may be the disadvantages of lead activity molecules
- may be peptidic
- poorly absorbed
- rapidly cleared - may have poor drug like properties and poor pharmacokinetics profile
- final drug may only be barely similar to original substance
what are the strategies for discovery of lead activity molecules
- exploitation of biological information
- improvement of existing drugs
- systematic screening
- planned research and rational drug design
what does exploitation of biological information involve
- study of natural products
- study of indigenous medicines (ethnopharmacology)
- clinical observation of side effects of medicines
- observations made in other scientific studies- animals and plants
- activities of industrial chemical products
what are natural products known as
- medicines- opium, atropine, cocaine (local anaesthetic)
- toxins and poisons- snakes, scorpions
- hallucinogens- alcohol, atropine
why were sympathomimetics discovered
a shortage of the drug ephedrine led to the development of amphetamines and other sympathomimetics
what is bothrops jararaca
- brazilian pit viper
- venom contains peptides
- known to be ACE inhibitors and bradykinin potentiators
- pro containing dipeptide inhibitors worked best in vivo
what does ethnopharmacology involve
- neuromuscular blocking agents
- atracurium
- artemisinin
what is artemisinin used for
- active substance in TCM
- used for chloroquine resistant malaria
what are the properties of procaine
- rapidly metabolised
- has CNS side effects
what are the properties of procainamide
- resistant to esterases
- less lipid soluble
- fewer CNS side effects
what are the properties of metoclopramide
- effective antiemetic
- high doses can give dystonic reactions
what are the properties of chlorpromazine
- antipsychotic
- also antiemetic
what are the properties of sulpiride
- effective antipsychotic agent
- lacks the sedating properties of chlorpromazine
give examples of observations made in other scientific studies
- anticancer alkaloids from catharanthus roseus tested for antidiabetic activity
- rats used died of septicaemia due to leukopenia
- vincristine, vinblastine identified as potent anti leukaemia drugs
give examples of activities of industrial chemical products
nitroglycerin gave workers headaches
- potent vasodilator
- isosorbide mononitrate and isosorbide dinitrate used in treatment of angina
what is involved in improving existing drugs
- seek to achieve improved
- potency
- selectivity
- safety
- duration of action
- formulation more easily handled by healthcare staff or more acceptable to patient - competing with market leader may be financially advantageous
- target is already defined
- market is already established
- clinical trials have good reference point
describe how B lactams were improved
- penicili=lins
- side chain modifications and b lactam cycle modifications
- allows for different selectivity of activity
describe how H2 blockers were improved
- ranitidine became market leader
- cimetidine inhibits CP450
describe how ‘consoles were improved
- fungistatics inhibit ergosterol biosynthesis
- fluconazole is safe via oral route
what is involved in systematic screening
- seek to test as many different compounds as possible
- sources of test compounds
- natural products
- chemical libraries - need assay systems that are fast and reliable
give examples of drugs derived from screening dyes
- chloroquine- antimalarial
- trypanosomiasis- sleeping sickness in Africa
- bendroflumethiazide and furosemide- diuretics
- benzodiazepines- anxiolytics and hypnotics
what is high throughput screening
screen a large number of small molecule compounds for interaction with the target system
- hope to find at least one hit on the target system
what are the advantages of high throughput screening
- assay system is immobilised
- many replicates in well plates
- highly automated
- liquid handling
- detection of response
- presentation and analysis of data - very large automated robotic systems
- capable of screening millions of samples per day
what is combinatorial synthesis
a process to prepare large sets of organic compounds by combining sets of building blocks
what is the goal of creating molecular libraries
to synthesise and test as many molecules as possible in as few as possible steps
- an attempt to produce very large libraries for screening
what are the problems with combinatorial chemistry
- working out what you have in the library
- working out which molecules are active- testing many molecules
- low hit rates
- high costs
- low quality hits
- poor bioavailability
- toxicity - chemically reactive, false positives
- problems with the chemistry
- individual chemical reactions shouldn’t yield alternative products
- should be high yielding at each step
give examples of successes from high throughput screening/combinatorial chemistry
- insulin mimetics
- thrombin inhibitors
- selective COX 2 inhibitors
what is fragment based lead discovery
- libraries of fragments of drug molecules are screened
- RMM <300
- logP <3
- hydrogen bond donors and acceptors <3 - fragments that show binding to a target are selected for further development
- usually low affinity
- multiple fragments can be combined - better success rate than combinatorial chemistry
what is involved in planned research and rational drug design
- identify a target or biochemical system
- attempt to address the target/system directly
- use endogenous molecules as a starting point (lead)
give examples of antimetabolites
molecules that are dihydrofolate reductase inhibitors
- trimethoprim- antibacterial
- 6-mercaptopurine- anticancer
- azathioprine- immunosuppressant
describe the difference between cortisol and prednisolone
prednisolone has increased glucocorticoid activity and reduced mineralocorticoid activity compared to cortisol
what are endogenous biochemicals
- manipulating the structure of an endogenous molecule could give drugs with improved performance
- preparing mimics of endogenous molecules can be used to disrupt physiological processes
- b blockers
- H2 antagonists
- ACE inhibitors
is a lead activity molecule beneficial
has little use
- needs to be transformed into a new chemical entity
what are the advantages of new chemical entities
molecules by design typically have better
1. pharmacodynamic properties- better selectivity/potency
2. pharmacokinetic properties- ADME
3. physicochemical properties- stability, formulation
4. toxicological properties
5. patentability- opportunity to recover development costs
