13/14 - Chemistry of Lipid Drugs Flashcards
5-a-steroid
Plate / FLAT
5-B-steroid
Cholic Acid
has a KINK
Prenyl Pyrophosphates
SUPPLY SIDE
of the
Cholesterol Biosynthesis
Include:
HMG-SCoA Reductase –> Melavonate
PHOSPHATES + ATP
Steroid Formation
Ianosterol
Intermediate Steps
of
Cholesterol Biosynthesis
SQUALENE
IANOSTEROL
Cholesterol as a SUBSTRATE
ACAT & LCAT
Cholesterol Fatty Esters
- *HDL Cholesterol –> ACAT**
- *(Acyl-Coa Acyl Transferase)**
- *EXCESS Cholesterol <–> LCAT**
- *(Lecithin Cholesterol Acyl Transferase)**
Formation of Bile Acids
from Cholesterol
DEMAND side of the equation
Catabolism of Cholesterol
BILE ACID** = **SURFACTANT / EMULSIFIER
Lipoproteins
LIPID CARRIERS** for **Cholesterol** & **TGs
Transport lipophilic compounds
Lipophilic CORE
Cholesterol Esters + TGs
Surrounded by more Hydrophilic Lipids
Phospholipids + non-esterfied cholesterol
&
Proteins
apolipoproteins
Types of Lipoproteins
5 Main Lipoproteins classified based on their DENSITY
HDL
MOST DENSE = protein rich
LDL
IDL
VLDL
- *CHYLOMICRONS**
- least dense* = lipid rich
Apoprotein
Recognition sites for Receptors
for
lipoproteins = carriers for TG / Cholesterol
LDL Consistancy
40nm = 1000x smaller than eukaryotic cell
SINGLE APO-B100 PROTEIN
wrapped around
1500 Cholesterol Ester molecules
500 unesterfied Cholesterol
800 Phospho lipids
Methods to CONTROL Cholesterol
↑Catabolism of cholesterol
↓GI uptake of Cholesterol
↓Fat uptake from GI
↓Diet with choleseterol
INHIBIT
major steps of biosynthesisb
Switches and Feedbacks in Cholesterol Uptake and Metabolism
4 of them
↑Free Cholesterol in cells –> Inhibits de novo synthesis
↑Cholesterol –> ↓uptake by
inhibiting expression of LDL receptor
Efficient bile acid RECYCLING:
_inhibits cholesterol synthesis & uptake_
Synthesis of cholesterol ESTERS
↑cholesterol synthesis
Which Early Cholesterol Drugs were
DISCONTINUED & WHY?
Triparanol** & **Diazacholesterol
inhbited LATE stage reductaces
Accumulation of:
Desmosterol in Serum & Liver
Severe ADR’s
Choleseterol synthesis
- should NOT be stopped at LATE STAGES*
- rather earlier stages*
Biochemical Mechanism of HMG-CoAR
Major Requirement
2 Steps:
reduction of HMG with NADPH occurs via a:
CHIRAL TETRAHEDRAL INTERMEDIATE
VVV
1st = ALDEHYDE –> 2nd = ALCOHOL
Reduction is stereoselective
OH group –> LYS side chain
interacts with
Statins vs HMG-CoA
Statins are:
Competitive with HMG
HMG-like Pharmacophore
but
NON-competitive with NADPH
TRANSITION STATE ANALOGUE
Pharmacore = most important, but acccesory affects are for:
affinity / rates of entry / availability / clearance & metabolism
Baycol = Cerivastatin
RECALLED due to:
SEVERE RHABDOMYOLYSIS
thought to be caused by drug’s hydrophobicity
incidence was 18-80x greater than other statins
COMBINED WITH FIBRATES = Bigger issue
Prodrugs due to the
CLOSED RING @ top
Pravastatin = OPEN RING = Active rug
Which Statin?
LIPITOR
Which Statin?
Rosuvastatin
Which Statin
Vytorin
Zocor + Zetia
MoA
Bile Acid Resins
- *ANION BINDING RESINS**
- NEG- Charge binds to **Bile Acids @ Intestine
- -> bile acid EXCRETION**
↓enterohepatic recirculation of bile:
↑Cholesterol 7-a Hydroxylase / ↑Cholesterol -> BA / ↑BA SECRETION
VVV
↑LDL & ↑VLDL REMOVAL + ↑LDL Receptors
↓LDL-C NET EFFECT
Bile Acid Sequestrants
MoA & Effects
Cholestyramine > Colestipol
MoA:
- *Bind -NEG- charged carboxylate group of BILE SALTS**
- *SEQUESTERING** them from intestinal lumen –> excreted
- stopping BILE SALT RECYCLING*
↑Cholesterol conversion into Bile Salts
↓LDL Cholesterol
good with statins, not with fibrates
Fibrates
MoA / Function
Fenofibrate / Gemfibrozil / Clofibrate
a-Substituted Carboxylic Acids
MoA:
PPAR-a + Fibrate binds RXR
ternary complex = active transcription factor
Activation of PPAR-a = nuclear transcription factor
induces expression of a number of genes involved in
LIPID METABOLISM
↓Lipoxygenases&↓Cyclooxygenases
Good at ↑HDL&↓TGs
