Drug Discovery 2

Question 0

what was the observation made to discover beta blockers ?

Answer 0

activation of the adrenergic system increased sympathetic drive and oxygen consumption in cardiac tissue

Question 1

What is a discovery of a drug that used translational biology ?

Answer 1

discovery of beta blockers

Question 2

what was the concept behind the discovery of beta blockers ?

Answer 2

a drug that will specifically block the action of adrenaline at beta adrenoreceptors

Question 3

what did james black hypothesise?

Answer 3

that the blocking of the beta adrenoreceptors would reduce oxygen demand of the heart and therefore reduce the pain associated wiht angina pectoris

Question 4

what early observations were known about adrenaline?

Answer 4

injection caused tachycardia and increased blood pressure

Question 5

what could phenoxybenzamine do ?

Answer 5

it reverse the increased blood pressure caused by adrenaline but it could not reverse the tachycardia

Question 6

what did W.B. cannon define in the 1930s?

Answer 6

defined 2 chemical transmitters of the sympathetic nervous system, sympathin E and sympathin I which supposedly combined with adrenaline to produce excitatory or inhibtory responses
- not actually true

Question 7

what did raymond ahlquist propose in 1948 ?

Answer 7

proposed that adrenaline’s excitatory or inhibitory repsonses were caused by different receptors being activated - they were named alpha and beta

Question 8

what was james black clear goal ?

Answer 8

to find a beta receptor antagonist
he expected it to reduce pulse rates at rest and during exercie and hoped it would decrease the susceptibility of patients with angina

Question 9

what did james black know before his own discoveries ?

Answer 9

he knew that by adding bulk next to the amine end of the adrenaline molecule would result in a marked increase in beta selectivity
this produced isoprenaline

Question 10

what was significant about the catechol group of isoprenaline ?

Answer 10

it is reactive and air sensitive so therefore they tried to replace it to produce a longer acting agonist

Question 11

what did eli lilly do to isoprenaline ?

Answer 11

he replaced the -OH with -Cl to try and improve the stability of isoprenaline but this caused a reduction in efficacy
it produced dichloroisoprenaline (DCI) = weak partial agonist that antagonises adrenaline

Question 12

what compound did james black start from ?

Answer 12

DCI

Question 13

what did black and stephenson do to DCI ?

Answer 13

replaced the Cl groups with another ring system to produce pronethalol
this was the first beta blocker
- it decreased heart rate in humans and increased exercise tolerance in angina patients

Question 14

when was pronethalol launched and why was it removed ?

Answer 14

released in 1963

discarded because it caused thymic cancer in mice

Question 15

what was inserted to ensure the hydroxyl and amine groups stayed in the same orientation ?

Answer 15

an oxymethylene bridge

Question 16

what did the insertion of the oxymethylene bridge produce ?

Answer 16

propranolol
it moved the appendage to C1 position
launched in 1965 but had carcinogenic properties

Question 17

what were the problems with propranolol ?

Answer 17

HAS LOCAL ANAESTHETIC PROPERTIES
- found to be caused by (+) stereoisomer in original properties
VIVID DREAMS
- lipophilic so it could cross the BBB
BRONCHO-CONSTRICTION WHICH IS VERY DANGEROUS IN ASTHMATICS
- excellent selectivity for beta receptors but couldnt distinguish between 1 and 2

Question 18

what was developed from propranolol ?

Answer 18

practolol
the 2nd ring was replaced with a para acetamido substituent
this is beta-1 selective and devoid of local anaesthetic side effects

Question 19

when was practolol launched and why was it withdrawn ?

Answer 19

launched in 1970 but withdrawn in 1975 due to serious side effects

Question 20

what was developed from practolol ?

Answer 20

atenolol
launched in 1976
block buster drug

Question 21

what are the other derivatives of atenolol?

Answer 21

tenormin
lopressor
metoprolol
carvedilol
inderal
bisoprolol
nebivolol

Question 22

what was the only slight disadvantage of atenolol ?

Answer 22

it had a long acting nature so it wasnt as useful in acute emergency care

Question 23

what was the reason behind discovery of a new shorter acting atenolol ?

Answer 23

in acute myocardial infarction

• lack of oxygen to the heart causing damage
• therefore adrenergic excitation of the heart would exacerbate the damage
• therefore the use of an adrenergic blockade is beneficial to reduce oxygen demand
• but damaged heart may also require adrenergic driive for contraction so an ultra short duration blocker would give clinicians more control

Question 24

what was atenolol modified to ?

Answer 24

esmolol - it had a shorter half life giving clincians better control
- hydrolysis at the ester bond by enzymes in erythrocytes results in a half life of 9 mins

Question 25

what happens when you stop infusing esmolol ?

Answer 25

its effects are stopped due to its very short half life

Question 26

what is a good example of transitional medicine?

Answer 26

esmolol because it was a clinicial requirement which lead to its discovery

Question 27

what are the 3 parts of discovery phase in modern drug discovery and development ?

Answer 27

1st ends with high throughput screen and the output of this is HITS
2nd results in one or more lead compounds
3rd results in the candidate drug which then moves into development

Question 28

what are the 2 parallel strands in the 1st stage of the discovery phase?

Answer 28

chemical= choosing/preparing the compound and libraries for screening 
biological= identifying/validating the target, developing the screening assays

Question 29

what is included within the chemical strand ?

Answer 29

synthetic and natural compound libraries
in silico filtering and custom synthesis of combinatorial libraries
in silico drug design and virtual screening to produce focused library synthesis

Question 30

what is part of the biological strand ?

Answer 30

target identification leads to…
target validation which leads to…
assay development and HIT valildation