Small Molecule Based Drug Design: SARLead Compound Identification - PowerPoint PPT Presentation

Title: Small Molecule Based Drug Design: SARLead Compound Identification


1
Small Molecule Based Drug Design SAR/Lead
Compound Identification

• Objectives A drug's pharmacological activity is
  inherently related to its chemical structure. 
  Upon completion of this lecture the student will
  know how small changes in chemical structure can
  lead to significant changes in biological
  activity, with emphasis on the sulfa drugs.  In
  addition, the student will learn traditional
  approaches used for the identification of lead
  compounds in the drug discovery process.

2
Structure-Activity Relationships (SAR)

• Crum-Brown and Fraser, 1868
• Richardson
• Structurally specific drugs
• Structurally nonspecific drugs
• Sulfa drugs good example of SAR     
  antibacterial     diuretics      antidiabetic

3
Sulfanilamide and general antimicrobial core
1) R SO2NHR' or SO3H 2) amino and sulfonyl
groups are para 3) anilino (benzene-NH2) amino
group may be unsubstituted (or substitutent
removed in vivo via metabolism of the drug) 4)
replacement of central benzene ring or additional
substituents diminishes activity 5)
N'-monosubstitution on SO2NHR' increase potency
(especially with heteroaromatic groups) 6)
N'-disubstitution on SO2NHR2' leads to inactive
compounds
4
General sulfanilamide antidiabetic agent core
X O, S or N incorporated into a heteroaromatic
ring or an acyclic structure
5
Diuretics
hydrothiazides 1,3-disulfamyl group R'' is an
electronegative group (Cl, CF3, NHR)
"High ceiling" type 1-sulfamyl-3-carboxy groups
R'' is Cl, Ph, or Ph-Z (Z O, S, CO or NH) X
located at position 2 or 3 (NHR, OR or SR)
6
Lead Discovery

• Bioassay
• in vitro versus in vivo
• Need multiple bioassays
• Activity, Potency, Binding

7
Lead Discovery

• Traditional, Folklore and Natural
  ProductsPenicillin, Librium
• Random screeningnatural products (grind and
  find)NCI databaseChemical geneticssoil samples
• Nonrandom screeningSimilar structural
  featuresCombinatorial chemistry

8
Combinatorial Chemistry

• Synthetic chemistry approach where a number of
  chemical building blocks are included in a
  reaction mixture to "randomly" produce a wide
  variety of chemical compounds.  These chemical
  compounds are then subject to experimental high
  throughput screening approaches to identify
  potential lead compounds.

9
Lead Discovery Drug Metabolism
Reduction of Sulindac
Reduction of Prontosil
10
Lead Discovery Clinical Feedback/Observation
1) Tesicam2) Sudoxicam3) Piroxicam