Structure-Activity-Relationships (SAR

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Structure-Activity-Relationships (SARs)

• Once a lead has been discovered, it is important
  to understand precisely which structural features
  are responsible for its biological activity (i.e.
  to identify the pharmacophore)

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The pharmacophore is the precise section of the
molecule that is responsible for biological
activity
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• This may enable one to prepare a more active
  molecule
• This may allow the elimination of excessive
  functionality, thus reducing the toxicity and
  cost of production of the active material
• This can be done through synthetic modifications
• Example R-OH can be converted to R-OCH3 to see
  if O-H is involved in an important interaction
• Example R-NH2 can be converted to R-NH-COR to
  see if interaction with positive charge on
  protonated amine is an important interaction

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Link
Link
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Next step Improve Pharmacokinetic Properties

• Improve pharmacokinetic properties.pharmacokineti
  c The study of absorption, distribution,
  metabolism and excretion of a drug (ADME).
• Video
• exerciseMedicationDistributiontitleMedication2
  0Absorption,20Distribution,20Metabolism20and20
  Excretion20Animationpublication_ID2450

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Metabolism of Drugs

• The body regards drugs as foreign substances, not
  produced naturally.
• Sometimes such substances are referred to as
  xenobiotics

• Body has goal of removing such xenobiotics from
  system by excretion in the urine
• The kidney is set up to allow polar substances to
  escape in the urine, so the body tries to
  chemically transform the drugs into more polar
  structures.

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Metabolism of Drugs (cont.)

• Phase 1 Metabolism involves the conversion of
  nonpolar bonds (eg C-H bonds) to more polar bonds
  (eg C-OH bonds).
• A key enzyme is the cytochrome P450 system, which
  catalyzes this reaction

RH O2 2H 2e ? ROH H2O
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Mechanism of Cytochrome P450