Structure-Activity-Relationships (SAR’s) 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”)

The pharmacophore is the precise section of the molecule that is responsible for biological activity

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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Next step: Improve Pharmacokinetic Properties Improve pharmacokinetic properties. pharmacokinetic = The study of absorption, distribution, metabolism and excretion of a drug (ADME). Video exercise=MedicationDistribution&title=Medicatio n%20Absorption,%20Distribution,%20Metabolis m%20and%20Excretion%20Animation&publicati on_ID=2450

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.

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 + O 2 + 2H + + 2e – → ROH + H 2 O

Mechanism of Cytochrome P450