Drug Discovery

Question 1

whats overall process for drug discovery?

Answer 1

Question 2

where is failure most common of drug discovery? where cost most?

Answer 2

Question 3

what are most drug targets? what specifically?

Answer 3

receptors: concerned directly and specifically in chemical signalling between and within cells

specifically: target GPCRs - and are agonists or antagonist

Question 4

what would a GPCR agonists and antagonist do?

how many approved drugs target GPCRs?

Answer 4

GPCR agonist: mimic effect of hormone / NT

GPCR antagonist: block effect of GPCR

700 approved drugs target GPCR

Question 5

what are class A orphan receptors?

Answer 5

the largest GPCR class, exhibit wide tissue distribution,

dont know what the ligand is for them

Question 6

how do you do target selection?

Answer 6

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

Question 7

what are the different types of drug (basic) do u use?

Answer 7

Question 8

what is a racemic drug?

Answer 8

racemic mixture: has both sterioiosmers of compound

Question 9

what is thalidomide? how was it involved in tragedy?

Answer 9

• 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

Question 10

how do you generate a drug that hits target?

Answer 10

• 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)

Question 11

what is structure activity relationships? (SAR)

Answer 11

changing chemical groups of coumpound changes the activity

Question 12

what happens in drug screening?

Answer 12

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?**

Question 13

what would ideal drug characteristics be?

Answer 13

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

Question 14

how do we determine safety of compound ? (preclinical)

Answer 14

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

Question 15

how you estimate metabolic stability in vitro?

Answer 15

compound &:

• different cyttochrome P450 enzymes
• preprations of human liver

also work out half life using above method

Question 16

what do you have to be aware of if create a drug which is metabolised by P450 enzymes?

Answer 16

existing drugs which inhibit P450 enzyme can cause negative impacts when given in combination with new drug

Question 17

PD - preclinical ?

Answer 17

animal models: sometimes v useful, sometimes not representative of human physiology

so some preclinical studies arent useful

Question 18

what is the nuremburg / helsinki legacy?

Answer 18

• 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

Question 19

phase 1 / 2 / 3 clinical trials?

Answer 19

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

Question 20

what is regulator dilemma?

Answer 20

want access to drugs quickly, but want to maximise safety

Question 21

what is authorisation process decided upon?

Answer 21

safety, quality and efficacy: risk:benefit

NOT cost

Question 22

how can we reduced death and suffering of marketed drugs?

Answer 22

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

Question 23

how do we decide which drugs to pay for?

Answer 23

NICE - National Institude for Clinical Excellence

• difference in local areas: postcode lottery
• drugs needs to work and cost effective

Question 24

* why do we get increasing placebo responses in pain trials? *

what does this mean re pharmas?

Answer 24

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

Question 26

why do pharama argue that antibiotics arent worth researching?

Answer 26

• Antibiotics difficult to discover and don’t command high prices
• Eg. $100,000 for cancer drug vs ‘a few thousand $’ for an antibiotic
• Antimicrobial for multi-drug-resistant bacteria limited to very small population

therefore we need new commercial model to give return on investment, not based on prescriptions sold

Question 27

what are some success stories of pharma?

Answer 27

Life Expectancy

• >30 years ↑ (20th century) • death from heart disease ↓ by ~60% (Americans; since 1975) • 5-year survival rates for cancer ↑ from 50% to ~70% • life span ↑ worth ~half national GDP (between 1970-98) - helped drive down rates of functional disability, so people living longer & better

Cost-Effectiveness

• In last 40 years, medicines halved hospital admissions for 12 major diseases • New cardiovascular medications in past 30 years eliminated 10’s of 000’s of costly surgeries/ hospitalizations • Medicines kept 000’s of patients with mental illnesses from institutional confinement for months/ years - often at taxpayer expense

Economic Value

• Bioscience industry employs ~1.3 million Americans & supports 7.5 million jobs across U.S. economy