Ballatore

Question 1

Common Descriptors in Drug Development

Answer 1

• pKa (for ionizable molecules) [acidity]
• logP and logD (octanol/water)
• Polar Surface Area (PSA) [permeability / dipole]
• Molecular weight (WT) [want <500]
• H bond count (donors/acceptors)
• # of Rotatable bonds

Question 2

Strategies for Optimization Process

Answer 2

• Homologation [add/take away carbon]
• Rigidification [constrain analogues, better binding affinity]
• Isosteric Replacements
• Use of -F in medicinal chemistry: changes liphophilicity, inductive effect, blocks metabolism
• Prodrug approaches

Question 3

Rigidification (constrained analogs)

Answer 3

~ One of the consequences of the binding of a ligand to a receptor is the loss of conformational freedom, which results in an entropic penalty

~ Conformationally constrained analogs are popular tactics to impose the bioactive conformation

Question 4

Bio-isosteric replacements

Answer 4

Bioisosteres are groups or molecules which have chemical and physical similarities producing broadly similar biological properties

Structural novelty - identify patentable “me too” drugs

Question 5

Fluorine uses

Answer 5

• Changes lipophilicity / pKa
• Influence on conformation
• Different types of rxns
• Blocks metabolism
• Inductive effect

Question 6

Prodrugs

Answer 6

• Identify the issue with the parent drug
  • Chemical/Biochemical considerations: activation mechanism, need a “handle” in the drug’s structure that could be
  exploited to append promoieties, identify appropriate combination of linkers and promoiety
• A prodrug should be shelf-stable but should provide
  adequate/predictable release of the drug in vivo