chemistry of statins

what are the functions of cholesterol?

steroid hormones
bile acids
biological membranes

cholesterol is the precursor for many hormones including

sex hormones
tissue growth hormones
adrenocortical hormones

what is cholic acid's role

added to emulsify water insoluble foods

What is the role of cholesterol and how does it relate to cardiovascular risk?

• Role: Important for biosynthesis and cell membrane structure.

• Transported by LDLs (to cells) and HDLs (from cells to liver).

• High LDL or low HDL levels → increased mortality.

• Can cause fatty plaques → risk of atherosclerosis, clots, stroke, heart attack.

what is the structure of cholesterol?

• OH group is polar,hydrophillic so can do hydrogen bonding

• alchohol can be HBD+HBA

What are the 3 main phases of cholesterol biosynthesis?

1. Formation of mevalonic acid.

2. Conversion of mevalonate → farnesyl pyrophosphate.

3. Condensation of two farnesyl pyrophosphate units → squalene.

How is cholesterol production regulated in the body?

• Key enzyme: HMG-CoA reductase.

• Regulation occurs via:

  • Kinase activity (phosphorylation/inactivation)

  • Transcription & translation (enzyme synthesis)

  • Enzyme degradation

• Feedback control: Regulated by cholesterol concentration.

How do statins work in cholesterol biosynthesis?

• Target enzyme: HMG-CoA reductase (rate-limiting step).

• Mechanism: Block the reduction of HMG-CoA → mevalonic acid in Phase 1.

• Chemistry: Involves two reduction steps to form mevalonate.

• Effect: Lowers cholesterol synthesis in the liver.

• But cholesterol can still be obtained from our diet.

How does HMG-CoA bind to its enzyme during catalysis?

• Positively charged Lys-735: forms ionic bond with substrate

• Hydrogen bonds: Ser-684, Asp-690, Lys-691 stabilize substrate

• Hydrophobic interactions: substrate fits into narrow hydrophobic slot

What is the general structure and key feature of Type I statins? Lovasaatin and simvasattin

• Structure: Polar “head” + hydrophobic moiety (including decalin ring)

• Prodrugs: Lovastatin and Simvastatin contain a lactone ring that is hydrolysed to form the polar head

Why are lovastatin modifications needed in drug design?

Statins are competitive inhibitors, so high levels of HMG-CoA can reduce their effectiveness.
- Modified versions of lovastatin are made to bind more strongly and stay longer in the enzyme’s active site, so the drug works better and lasts longer.

What are the main structural modifications of lovastatin?

• Change the side chain (ether side-chain modifications)

• Extend the lactone ring (make it slightly bigger)

• Convert it to a mevalonate-like form (adjust the shape/stereochemistry at the OH carbon)

What are the main shortcomings of Type I statins?

• type 1 stations are liphillhic so cross bbb cns related side effects:sedation. msucle pains . Gi issues

• difficult to synthesize, mainly from mould cultures → semi-synthetic

• Structural complexity: many asymmetric centres

Type II Statins – How does hydrophobicity affect their action?

• Less hydrophobic statins target liver cells more specifically and have lower side effects.

• Reason: Less hydrophobic statins don’t cross cell membranes easily, but liver cells have transport proteins for statins.

Why do statins mainly act in the liver?

• Majority of cholesterol synthesis occurs in liver cells.

• Liver cells express specific transport proteins for statins.

Common side effects of statins

• Myalgia (muscle pain) is common.

• Severe muscle toxicity = rhabdomyolysis, which can be fatal.

Type I vs Type II statins – structural features & side effects

Feature	Type I Statins	Type II Statins
Origin	Natural / semi-synthetic	Fully synthetic
Lipophilicity	More lipophilic (hydrophobic)	Less lipophilic
Cell entry	Passive diffusion across membranes	Transported into liver by proteins
Targeting	Enter many tissues (including muscle)	More liver-selective
Side effects	Higher risk (especially muscle toxicity)	Lower risk
Reason for side effects	Can enter muscle cells easily	Limited entry into non-liver cells

what makes the differnces in the lipohillicity?

• type 1 : Contain a decalin ring or bulky non-polar groups → increases hydrophobic character.+lipophhilic

• type 2: fully synthetic;Have larger polar/ionic groups attached to the ring system (like fluorophenyl, pyrimidine).don’t have the decalin ring

• These increase hydrophilicity,

Type II statins – structure & side effects

• Type II statins are less lipophilic overall than Type I, but they still retain a hydrophobic core (aromatic or cyclic rings) that is essential for HMG-CoA reductase binding.

• The difference is that Type II statins have additional polar/ionic groups attached to the hydrophobic core. These reduce overall lipophilicity,

Statins – Mechanism of Action

• Compete with HMG-CoA → block the enzyme (HMGR)

• Polar head mimics HMG-CoA → binds in the active site

• Hydrophobic part adds extra binding → stronger attachment

• Bind very tightly but don’t react → act as transition-state analogues

• Mimic reaction intermediate (mevalonate-like) → effectively stop the enzyme

Atorvastatin – Binding Interactions

• Polar head mimics HMG-CoA → forms:

  • H-bonds with Ser-565

  • Ion–dipole interaction with Arg-590

• Hydrophobic part → enzyme changes shape to form a pocket

• Methylethyl group → fits same site as decalin ring (Type I statins)

• Fluorophenyl group → interacts with Arg-590 (important contact)

Rosuvastatin – Binding Interactions

• Polar head mimics HMG-CoA → H-bonds with Ser-565

• Sulfone group → extra H-bond with Ser-565 + interacts with Arg-568

• Hydrophobic part → fits into flexible pocket

• Result: stronger binding → high potency

Key structural features of a statin (SAR)

• Polar head group → mimics HMG-CoA → essential for binding to HMG-CoA reductase

• Hydrophobic core → fits into enzyme pocket → stabilizes binding

• Stereochemistry →correct 3,5-hydroxyl positions needed

• Ring system & substituents → modulate potency and selectivity

Statin metabolism for atorvastatin, pitavastatin and fluvastatin they have

hydroxylation on aromatic rings

what is the primary metabolite?

why is the OH group the primary site of oxidation

OH group - site of oxidation

The way CYP450 interacts with the drug structure

why is the para- position favoured

it allows for stable intermediate formation as it is electron rich due to resonance effects from the adjacent heterocycle

Atorvastatin – Primary Metabolism & Activity

forms ortho- and para-hydroxy active metabolites

• Fluorophenyl: –I/–R effect stabilizes transition state; fits hydrophobic pocket → stronger binding

• Pyrrole: conjugated ring, +R effect, planar → optimizes enzyme interactions

• Overall: both stabilize binding → potent HMG-CoA reductase inhibition