Theme 6 Lecture 23 Flashcards
Acidic and benzene
What are the key steps in the lead optimisation of Losartan?
Angiotensin receptor 2 antagonists
Optimisation process includes adding an additional aromatic ring and retaining the acidic moiety
positive
What did the addition of the new benzene ring do?
This addtion interacted with the positive receptor space and interacts with tyrosine hydroxyl and aspartyl carboxylic acid.
high
What was distinct about the selectivity of the drug.
The selectivity was very high, but the potency wasnt as 7g had toi be injected in to rats which is the human equivalence.
What does low IC50 indicate?
High potency, and IS A CONC OF SUSBTANCE THAT it takes to inhbit 50% if the biological activity.
simple changes=carbonyl, ether and thioetehr
Exploration of Amide Isosteres and Biphenyl Scaffold in Drug Optimization
Amide linkage caused an increase in the IC50
Thus simpler changes like carbonyl, ether, and thioether maintained similar potencies to the original amide
1c
What is homologation?
It is the addtion of 1c unit to a carbon chain
R2,R4,X Liners and bioactivity evidence
describe the SAR summary on slide 8
R2: A butyl group is optimal; substituting it with bioisosteres like S-ethyl or S-propyl results in lower affinity.
R4: Substituents such as Cl, CH2OH, or CH2OAc are similarly tolerated, showing versatility at this position.
X Linkers: The optimal linker length is between 0-1 atoms, crucial for maintaining proper spatial conformation and activity.
Bioactivity Evidence: The compound series shows effective blood pressure reduction, as demonstrated by the blood pressure graph.
pka
What were the carboxyilic acid roles in the bioisosteres
The role was it maintains the pka range
What is ED30?
The ED30 is the dose of the drug that produces 30% of the maxium effect.
Have a look at exercise 1 and explain to me simply what is going on?
Part a) clear changes of groups like addition of OH, OXYGEN OR A RING.
Part b) Make groups already work that shouldnt interfere with the 3d relationship and directionality.
E.g. like addition of rings.
Cimetidine background
Trying to find drugs purely selective for H2 which is found on gastric pareital cells.
What was the initial design for cimetdine and approach
Based off its natural ligand of histamine
Substitutions on imidazole ring
Homologation and substituions on side chain
Finally 4-methylhistamine was made.
Nitrogen,imidazole,sharing, electron donat
How did imidazole tautomerism influence the development of Cimetidine?
Adding electron withdrawing group like nitrogen reduces bascity.
Imidazole is already basic due to tautermism.
Protonation allows for tautoermism across 3 atoms share a positive charge which increases basicity.
If you add an electron donating group like methyl, it counters the EW thus increasing the pka and basicity.
Poor bioavailabilty
What was the issue with Burimamide?
Was found to be selective for the H2 however in vivo assays were carried out in rats and it was not readily bioavailable in humans.
Addition of methyl, sulphu
How the methyl and sulphur impacted on metiamide
Addition of methyl allowed for tauteromerism, but was electron donating.
The sulphur had the electron withdrawing effect which balanced out (through inductive effect)
