Drug Discovery Flashcards
whats overall process for drug discovery?
where is failure most common of drug discovery? where cost most?
what are most drug targets? what specifically?
receptors: concerned directly and specifically in chemical signalling between and within cells
specifically: target GPCRs - and are agonists or antagonist
what would a GPCR agonists and antagonist do?
how many approved drugs target GPCRs?
GPCR agonist: mimic effect of hormone / NT
GPCR antagonist: block effect of GPCR
700 approved drugs target GPCR
what are class A orphan receptors?
the largest GPCR class, exhibit wide tissue distribution,
dont know what the ligand is for them
how do you do target selection?
combination of approaches of evidence from literature, academics, in-house research, genetic / RNA, comparitve genetics, assays
= needs to be novel AND meet unmet medical need
what are the different types of drug (basic) do u use?
what is a racemic drug?
racemic mixture: has both sterioiosmers of compound
what is thalidomide? how was it involved in tragedy?
- prescribed as sedative or hypnotic:
- S-thalidamide = effective sedative
- R-thalidamide = teratogenic (an agent that can disturb the development of the embryo or fetus)
both given - made disformities
how do you generate a drug that hits target?
- start from known compounds (43%)
- structure-based design
- random high throughput screen (29%) - screen lots of molecules and see which binds to target:
a) validate reagents and scale up
b) assay evaluation for HTS
c) HTS validation
(a-c = 6 months)
d) HTS
e) confirm hits (hit = binds to receptor)
f) investigate pharmacology of hits
(d-f = 3 months)
what is structure activity relationships? (SAR)
changing chemical groups of coumpound changes the activity
what happens in drug screening?
screening = designing the drug candidate
screen 1000s of molecules to final molecule, selecting for:
- *- potency
- selectivity (AE)
- PK (long in body? absorbed? pass BBB? GI breakdown?)
- efficacy in animal model
- PD
- safe?**
what would ideal drug characteristics be?
high potency and no AEs
once daily, without accumulartion or breakdown to ative metabolites by oral or IV routes
brain penetrant
treat disease without tolerance or AEs
how do we determine safety of compound ? (preclinical)
toxicaology and safety assessment - in vitro and invivo tests:
in vitro: mutagenicity in bacteria, mammalian microsomal enzyme test
in vivo: normally in mice: toxicity on reproductive systems (2 generations), chronic studies: investigate carcinogensis, effects of metabolites
how you estimate metabolic stability in vitro?
compound &:
- different cyttochrome P450 enzymes
- preprations of human liver
also work out half life using above method
what do you have to be aware of if create a drug which is metabolised by P450 enzymes?
existing drugs which inhibit P450 enzyme can cause negative impacts when given in combination with new drug
PD - preclinical ?
animal models: sometimes v useful, sometimes not representative of human physiology
so some preclinical studies arent useful
what is the nuremburg / helsinki legacy?
- Voluntary consent of the subject (informed)
- Aims of the experiment are for the ‘good’ of society
- Good science, performed by qualified scientists, backed up by data in animals
- Minimise risk, suffering and injury
- Risks should not exceed benefit
- Experiment can be terminated by subject or researcher
- Protocol
phase 1 / 2 / 3 clinical trials?
Phase 1:
healthy volunteers, small numbers
• Immediate responses to new drug
• Small doses
• Escalated doses until effect seen
• Tolerability assessed
• Pharmacokinetics studied
• Short-term studies
• Single dose per volunteer usually
Phase 2:
• Patient groups
• Small numbers, studied intensively
• Pharmacological assessment - kinetics
• Efficacy- does it work in the clinical setting?
• Tolerability in target group - unwanted effects
Phase 3:
• More patients
• Studied less intensively
• Usually controlled designs
• Compare vs. established therapy (or placebo)
• Identify optimum dose
• Check methods of administration •
Establish indications for the drug
• Prepare for licensing of the drug
• Must establish a case for the new drug
• Negotiations with regulators (MHRA)
• Additional studies if required
what is regulator dilemma?
want access to drugs quickly, but want to maximise safety
what is authorisation process decided upon?
safety, quality and efficacy: risk:benefit
NOT cost
how can we reduced death and suffering of marketed drugs?
Pharmacovigilance: in Phase 4 studies
After initial licensing
• Extend indications for drug?
• Refine target group?
• Interaction studies - perhaps responding to case reports
• Why do some fail to respond?
• Continuous process
how do we decide which drugs to pay for?
NICE - National Institude for Clinical Excellence
- difference in local areas: postcode lottery
- drugs needs to work and cost effective
* why do we get increasing placebo responses in pain trials? *
what does this mean re pharmas?
larger and longer trials being run:
- longer trials: more opportunities for social support, education
- larger trials: relaxed elig. criteria?
- greater use of CROs
SO:
- less desire to undertake neuropathic pain research
- lots of closure of neuro departments
