Drug Discovery 2 Flashcards
(31 cards)
what was the observation made to discover beta blockers ?
activation of the adrenergic system increased sympathetic drive and oxygen consumption in cardiac tissue
What is a discovery of a drug that used translational biology ?
discovery of beta blockers
what was the concept behind the discovery of beta blockers ?
a drug that will specifically block the action of adrenaline at beta adrenoreceptors
what did james black hypothesise?
that the blocking of the beta adrenoreceptors would reduce oxygen demand of the heart and therefore reduce the pain associated wiht angina pectoris
what early observations were known about adrenaline?
injection caused tachycardia and increased blood pressure
what could phenoxybenzamine do ?
it reverse the increased blood pressure caused by adrenaline but it could not reverse the tachycardia
what did W.B. cannon define in the 1930s?
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
what did raymond ahlquist propose in 1948 ?
proposed that adrenaline’s excitatory or inhibitory repsonses were caused by different receptors being activated - they were named alpha and beta
what was james black clear goal ?
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
what did james black know before his own discoveries ?
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
what was significant about the catechol group of isoprenaline ?
it is reactive and air sensitive so therefore they tried to replace it to produce a longer acting agonist
what did eli lilly do to isoprenaline ?
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
what compound did james black start from ?
DCI
what did black and stephenson do to DCI ?
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
when was pronethalol launched and why was it removed ?
released in 1963
discarded because it caused thymic cancer in mice
what was inserted to ensure the hydroxyl and amine groups stayed in the same orientation ?
an oxymethylene bridge
what did the insertion of the oxymethylene bridge produce ?
propranolol
it moved the appendage to C1 position
launched in 1965 but had carcinogenic properties
what were the problems with propranolol ?
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
what was developed from propranolol ?
practolol
the 2nd ring was replaced with a para acetamido substituent
this is beta-1 selective and devoid of local anaesthetic side effects
when was practolol launched and why was it withdrawn ?
launched in 1970 but withdrawn in 1975 due to serious side effects
what was developed from practolol ?
atenolol
launched in 1976
block buster drug
what are the other derivatives of atenolol?
tenormin lopressor metoprolol carvedilol inderal bisoprolol nebivolol
what was the only slight disadvantage of atenolol ?
it had a long acting nature so it wasnt as useful in acute emergency care
what was the reason behind discovery of a new shorter acting atenolol ?
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
