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Title: Oral bioavailability of drugs-Lipinski and Webers rules
Description: Aimed at degree students studying modules in medicinal chemistry, these notes focus on Lipinski and Weber rules, which are predictors of good oral bioavailability of drugs.

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Lipinski  and  Veber  rules    
 
The  Lipinski  and  Veber  rules  are  rules  for  compounds  being  investigated  for  
drug  discovery
...
   
 
Lipinski  rules  
 
Lipinski’s  rules  of  5  are  as  follows…the  drug  should  have    
• A  molecular  weight  <500    
• A  value  of  logP<5    
• Less  than  5  –OH  or  –NH  groups  (hydrogen  bond  donors)  in  total      
• Less  than  10  O  or  N  atoms  in  total  (hydrogen  bond  acceptors    
 
Explained  
 
 
• A  molecular  weight  of  less  than  500
...
 Presumeably  due  to  compound  size    
• P  is  the  partition  coefficient,  a  measure  of  hydrophobicity
...
   
• 5  –OH  and  –NH  bonds,  and  10  O  or  N  atoms  is  to  determine  hydrogen  
bonding
...
 This  is  
key  to  its  water  solubility,  but  these  bonds  must  be  broken  if  it  is  to  cross  
the  lipid  membranes
...
   
• On  average,  commercial  drugs  have  molecular  weight  of  360,  an  average  
of  2
...
3  O  and  N  atoms,  and  a  lop  
value  of  1
...
   
 
Veber  rules    
 
Veber  et  al,  in  a  paper  released  in  2002,  proposed  the  following:    
• 10  or  fewer  rotatable  bonds  (though  if  its  less  than  7,  oral  bioavailabilty  is  
much  greater  than  7  or  more)    
• Less  than  12  H  bond  donors  or  acceptors  in  total    
• A  polar  surface  area  of  less  than  140  A  (angstroms)  squared    
• These  rules  don’t  give  a  molecular  weight  value  
 
Why  are  the  rules  important-­‐a  bit  on  oral  bioavailability    
 
There  are  many  different  drug  administrative  routes-­‐intravenous,  subcutaneous,  
intramuscular…but  arguably  the  best  is  oral,  because  it  doesn’t  involved  sticking  
a  needle  into  the  body  and  all  the  risks  associated  with  that
...
 Notably  digestion
...
   
 
Not  only  this,  but  the  drug  has  to  be  absorbed
...
   
 
However  this  has  to  be  finely  balanced
...
 Not  soluble  enough  and,  depending  on  the  compound,  it  
might  precipitate  somewhere  like  the  kidneys
...
 Not  soluble  enough  in  fats,  and  it  doesn’t  cross  the  
membranes
...
4  to  +5
...
 As  such  a  “rule  of  3”  has  been  
proposed  for  lead-­‐like  compounds,  which  allows  some  room  for  variation:    
• LogP  less  than  3    
• Molecular  weight  under  300    
• No  more  than  3  hydrogen  bond  donors  
• No  more  than  3  hydrogen  bond  acceptors    
• No  more  than  3  rotatable  bonds    
Known  compounds  that  people  want  to  investigate  for  potential  as  a  lead  
compound  should  fit  these  rules,  ideally
...
 This  requires  analysis  
of  the  pharmacophore  to  determine  the  optimal  structure  and  
interactions  for  the  target
...
   
• Rule  out  the  drug  from  use
...
 Some  drugs  don’t  conform  with  Lipinski  rules  
but  are  absorbed  anyway
...
 Antibiotics  and  lipid  soluble  vitamins,  
for  example,  are  absorbed  by  transporters,  or  in  the  case  of  the  vitamins,  
absorbed  with  lipids
...
   


Title: Oral bioavailability of drugs-Lipinski and Webers rules
Description: Aimed at degree students studying modules in medicinal chemistry, these notes focus on Lipinski and Weber rules, which are predictors of good oral bioavailability of drugs.