Antwi

• Prodrug


  A pharmacologically inactive compound that is converted to its active form through metabolism

  • By metabolizing enzymes within the body
  • Or via a nonenzymatic process
• There are three basic types of prodrugs

  1. Carrier-linked
  2. Bioprecursor
  3. Mixed
• Drug barriers (solutions):

  • Solubility (phosphates, sugar derivatives, amino acids. MAKE IT POLAR)
  • Absorption/bioavailability (Masking ionizable groups by adding alkyl/aryl groups and making esters)
  • Distribution (Target cell or specific transporters/enzymes, sugar derivatives)
  • Metabolism & excretion (Mask ionizable groups by adding alkyl/aryl groups and making esters)
  • Toxicity (Various prodrug methods)
• Carrier linked prodrugs have an inert carrier that is covalently coupled with active drug (e.g. esters, phosphates, amino acids, sugars)


  Helps with absorption
• Esters replacing carboxylic acids make drugs more lipophilic and improves oral bioavailability
• Esters and carboxylic acids trade places via esterase
• Phosphates can be used to increase water solubility by replacing an alcohol or ester with phosphatase
• This is a steroid

  
• Tamiflu is an inhibitor of neuraminidase for the treatment of influenza A and B. (Uses esters as carrier linked prodrugs)
• The bioprecursor prodrug show their action after undergoing metabolism reaction in the body 


  Very common for antiviral drugs
• Nucleosides are an example of bioprecursor prodrugs


  They don’t activate until they gain 3 phosphate groups, becoming nucleotides
• Mixed carrier-linked/bioprecursor drugs tend to involve attaching the drug to the carrier in a lab setting, then the molecule becomes bio-activated by metabolism in the body
• Diversity libraries contain synthetic molecules that are designed and synthesized to cover as much chemical space as possible and have no known target. Most compounds in this library contain sp3 and sp2 hybridized carbons.
• Focused libraries are smaller collections of compounds meant to show activity at a designated class of protein (target).


  Common targets include

  • Kinase inhibitors
  • GPCR antagonists/agonists
  • Ion channel ligands
  • Some select cellular pathway packages
• Fragment libraries are smaller than average compounds and are meant to be combined into larger “drug like” compounds.
• Fragments are typically one to two ring systems and some hetero atoms. They typically obey the rule of 3
• The process of fragment optimization involves “growing” and “linking”
• Natural product libraries contain chemical matter from plant, animal, and microorganism sources
• Natural product libraries are quite expensive compared to synthetic compound libraries due to availability and cost of included compounds
• Peptide libraries are predominantly used for studying cellular activities modulated by peptides. Cell surface receptors with peptide substrates are well suited to studying by this method
• Combining amino acids linearly (like in peptide libraries) leads to exponential rises in compound diversity and is the earliest example of library synthesis
• Solid-phase synthesis is a method in which molecules are covalently bound on a solid support material (resin bead) and synthesized step-by-step in a single reaction vessel utilizing selective protecting group chemistry.
• Advantages of soli-phase synthesis

  • Starting material bound to solid support
  • Intermediates remain bound to beads during synthesis
  • No isolation or purification
  • Excess reagents are used up or easily washed away
  • Beads can be mixed, leading to distinct product formation
• Combinatorial synthesis is a method of rapidly generating a series of compounds by treating multiple substrates with the same reagents simultaneously. The products can then be split and treated with different reagents to create a pool of diverse compounds
• Combinatorial synthesis can be carried out in solution but is typically performed on solid support
• Combinatorial synthesis involves the preparation of libraries of a very large number of compounds then, the libraries can be used to identify useful components
• Split pool synthesis is a combinatorial strategy in which compounds are split and treated with different reagents to create a pool of diverse compounds, then recombined and split again
• Split pool synthesis and parallel synthesis can easily be performed on non-peptide substrates
• Bead consideration factors heavily into solvent choice in split pool synthesis and can greatly limit synthetic flexibility
• In split pool synthesis, so long as functional group is conserved among all “building blocks”, substrates are compatible and can be combined
• In split pool synthesis, “building blocks” are low MW simple compounds that combine using simple, effective chemistry
• The key difference between split and parallel synthesis is that split synthesis uses a mixture of compounds for reactions, whereas parallel synthesis uses an individual compound for reactions
• Parallel synthesis frequently makes use of CombiBlocks which are multi—well heating blocks into which reaction vessels are placed
• In parallel synthesis, a hit compound can be broken down to two common, cheap, building blocks
• In parallel synthesis, if you treat 6 unique compounds with 4 other unique compounds, you end with 24 unique analogs of the compounds. 


  6 * 4 = 24
• Split-pool library development will generate bigger libraries of compounds faster and cheaper, but with less precision and assurance
• Parallel synthesis takes time to create small libraries but you know exactly what you made and can readily purify products
• High throughput screening allows for automated testing of large numbers of compounds. It is expensive but can lead to novel lead compounds for almost any target
• High throughput screening is the entry point into the drug discovery process (before hit identification and lead optimization)
• The two sides of high throughput screening are industry and academia. The differences are what you’d expect. Industry has more money and is therapeutic driven whereas academia has limited resources and is science driven