Sources of new drugs

Question 1

what is lead discovery

Answer 1

the process of identifying active new chemical entities, which by subsequent modification may be transformed into a clinically useful drug

Question 2

what is lead generation

Answer 2

strategies developed to identify compounds which possess a desired but non optimised biological activity

Question 3

what may be the disadvantages of lead activity molecules

Answer 3

1. may be peptidic
   - poorly absorbed
   - rapidly cleared
2. may have poor drug like properties and poor pharmacokinetics profile
3. final drug may only be barely similar to original substance

Question 4

what are the strategies for discovery of lead activity molecules

Answer 4

1. exploitation of biological information
2. improvement of existing drugs
3. systematic screening
4. planned research and rational drug design

Question 5

what does exploitation of biological information involve

Answer 5

1. study of natural products
2. study of indigenous medicines (ethnopharmacology)
3. clinical observation of side effects of medicines
4. observations made in other scientific studies- animals and plants
5. activities of industrial chemical products

Question 6

what are natural products known as

Answer 6

1. medicines- opium, atropine, cocaine (local anaesthetic)
2. toxins and poisons- snakes, scorpions
3. hallucinogens- alcohol, atropine

Question 7

why were sympathomimetics discovered

Answer 7

a shortage of the drug ephedrine led to the development of amphetamines and other sympathomimetics

Question 8

what is bothrops jararaca

Answer 8

• brazilian pit viper
• venom contains peptides
• known to be ACE inhibitors and bradykinin potentiators
• pro containing dipeptide inhibitors worked best in vivo

Question 9

what does ethnopharmacology involve

Answer 9

1. neuromuscular blocking agents
   - atracurium
   - artemisinin

Question 10

what is artemisinin used for

Answer 10

• active substance in TCM
• used for chloroquine resistant malaria

Question 11

what are the properties of procaine

Answer 11

• rapidly metabolised
• has CNS side effects

Question 12

what are the properties of procainamide

Answer 12

• resistant to esterases
• less lipid soluble
• fewer CNS side effects

Question 13

what are the properties of metoclopramide

Answer 13

• effective antiemetic
• high doses can give dystonic reactions

Question 14

what are the properties of chlorpromazine

Answer 14

• antipsychotic
• also antiemetic

Question 15

what are the properties of sulpiride

Answer 15

• effective antipsychotic agent
• lacks the sedating properties of chlorpromazine

Question 16

give examples of observations made in other scientific studies

Answer 16

• 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

Question 17

give examples of activities of industrial chemical products

Answer 17

nitroglycerin gave workers headaches
- potent vasodilator
- isosorbide mononitrate and isosorbide dinitrate used in treatment of angina

Question 18

what is involved in improving existing drugs

Answer 18

1. seek to achieve improved
   - potency
   - selectivity
   - safety
   - duration of action
   - formulation more easily handled by healthcare staff or more acceptable to patient
2. competing with market leader may be financially advantageous
   - target is already defined
   - market is already established
   - clinical trials have good reference point

Question 19

describe how B lactams were improved

Answer 19

• penicili=lins
• side chain modifications and b lactam cycle modifications
• allows for different selectivity of activity

Question 20

describe how H2 blockers were improved

Answer 20

• ranitidine became market leader
• cimetidine inhibits CP450

Question 21

describe how ‘consoles were improved

Answer 21

• fungistatics inhibit ergosterol biosynthesis
• fluconazole is safe via oral route

Question 22

what is involved in systematic screening

Answer 22

1. seek to test as many different compounds as possible
2. sources of test compounds
   - natural products
   - chemical libraries
3. need assay systems that are fast and reliable

Question 23

give examples of drugs derived from screening dyes

Answer 23

1. chloroquine- antimalarial
2. trypanosomiasis- sleeping sickness in Africa
3. bendroflumethiazide and furosemide- diuretics
4. benzodiazepines- anxiolytics and hypnotics

Question 24

what is high throughput screening

Answer 24

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

Question 25

what are the advantages of high throughput screening

Answer 25

1. assay system is immobilised 2. many replicates in well plates 3. highly automated - liquid handling - detection of response - presentation and analysis of data 4. very large automated robotic systems 5. capable of screening millions of samples per day

Question 26

what is combinatorial synthesis

Answer 26

a process to prepare large sets of organic compounds by combining sets of building blocks

Question 27

what is the goal of creating molecular libraries

Answer 27

to synthesise and test as many molecules as possible in as few as possible steps - an attempt to produce very large libraries for screening

Question 28

what are the problems with combinatorial chemistry

Answer 28

1. working out what you have in the library 2. working out which molecules are active- testing many molecules 3. low hit rates 4. high costs 5. low quality hits - poor bioavailability - toxicity 6. chemically reactive, false positives 7. problems with the chemistry - individual chemical reactions shouldn't yield alternative products - should be high yielding at each step

Question 29

give examples of successes from high throughput screening/combinatorial chemistry

Answer 29

1. insulin mimetics 2. thrombin inhibitors 3. selective COX 2 inhibitors

Question 30

what is fragment based lead discovery

Answer 30

1. libraries of fragments of drug molecules are screened - RMM <300 - logP <3 - hydrogen bond donors and acceptors <3 2. fragments that show binding to a target are selected for further development - usually low affinity - multiple fragments can be combined 3. better success rate than combinatorial chemistry

Question 31

what is involved in planned research and rational drug design

Answer 31

1. identify a target or biochemical system 2. attempt to address the target/system directly 3. use endogenous molecules as a starting point (lead)

Question 32

give examples of antimetabolites

Answer 32

molecules that are dihydrofolate reductase inhibitors - trimethoprim- antibacterial - 6-mercaptopurine- anticancer - azathioprine- immunosuppressant

Question 33

describe the difference between cortisol and prednisolone

Answer 33

prednisolone has increased glucocorticoid activity and reduced mineralocorticoid activity compared to cortisol

Question 34

what are endogenous biochemicals

Answer 34

- 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

Question 35

is a lead activity molecule beneficial

Answer 35

has little use - needs to be transformed into a new chemical entity

Question 36

what are the advantages of new chemical entities

Answer 36

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