Atorvastatin Flashcards
What is cholesterol, what percent is synthesised and dietary and how is it transported in the body?
Critical component of cell membranes and the precursor to all steroid hormones. 80% synthesised, 20% dietary and lipoproteins
What are the two types of lipoprotein and what do they do?
High density protect the cardiovascular system, low density cause atherosclerosis and coronary heart disease
What is the rate limiting step in cholesterol biosynthesis?
HMG-CoA reductase enzyme
Why could HMG-CoA reductase be an attractive drug target?
inhibiting the slowest step will slow down the production of cholesterol
What are the natural inhibitors and what semi-synthestic derivatives were then made?
Compactin and Lovastatin and then Simvastatin and Pravastatin were made.
What does HMG have interactions with?
H bond interactions with Asp690
What is needed for activity?
Correct spatial arrangement between the hydrophobic group and the delta lactone
What is the part responsible for activity of the drug mostly?
The top hydroxy lactone ring structure
What decreases the activity of the compactin?
Removal of the hydrophobic group
Who dominated the market and who looked at pyrrole as a template?
Merck and Parke-Davis
What two structures did they come up with at Parke Davis and what were their IC50 values?
> 100 uM and 2.8 uM.
What R groups were decided upon?
R1 = Fc6H4 and R2 = CH(CH3)2
What groups for R3 and R4 were found to be toxic? What was used instead?
Br and Cl. Ph as R3 and CONHPh as R4
What were the IC50 values of the Racemate, RR and SS enantiomers?
0.025 mM, 0.007 mM and 0.440 mM.
In what form is it sold?
As the calcium salt
