Structural Properties 4 Lecture Flashcards
Define bioisosteres
Substituents or functional groups that have similar chemical and/or physical properties and which produce broadly similar biological properties
- Lead compound optimization approach
Biososterism is used for what?
Reduce toxicity
Increase metabolic stability
Improve solubility and or ADME properties
Provide greater target selectivity
Simplify synthesis
Allow compounds based on fragment hopping to be patented
What parameters where effected?
Size (radius) Conformation (cis vs trans) EDG EWG and resonance effects Polarization H bond forming capacity pKa Solubility Hydrophobicity Reactivity Stability
What are two major forms of biososteres?
Classical and Non-classical
What are classical biososteres?
Monovalent
Divalent (take an ether in the middle of the drug molecule and replace it with an NH- proton donor)
Trivalent (no H on it but has 3 bonds)
Tetravalent (get rid of C, put N in there, potential to ionize and ability to HBA)
Define antibacterials?
Aromatic group may be replaced by heterocyclic aromatics to produce active and resistance free compounds
What are non-classical bioisosteres?
Exchangeable groups
Cyclic vs non-cyclic
Do not rigidly comply with the steric and electronic properties
What is CF3?
Non-classical bioisostere for a methyl group due to size but has widely different electronic properties
Define Stereochemistry
the specific spatial arrangement of a compounds functional groups and carbon backbone in 3D space
How does stereochemistry play into pharmacological properties of drugs
Any changes will alter the interactions of functional groups
Isomers can have different properties and can differ in pKa, logP
- Both alter pharmacological properties of the drugs
What are the three main stereochemical factors influencing the pharmacological profile?
Conformational isomers
Geometrical isomers
Optical isomers
Define conformational isomers
Non-identical spatial arrangement of atoms and groups in a molecule that result from rotating around a single bond
- Almost all drugs have more than one conformation and can bind to different receptors
Define geometric isomers
Occurs as a result of restricted rotation about a chemical bond owing to double bonds or a rigid ring system in the molecule
Not mirror images; different physicochemical properties and pharamacological activity bc different distance between functional groups
General do not fit in the same receptor
When do axial and equitorial positions appear?
6 membered rings do not exist as hexagons
- Adopt chair conformation to minimize angles and torsional strain
- -> substituents occupy orientations
Define optical isomers
Compounds that contain at least one chiral carbon atoms
Define dextrorotatory
(+)
Isomer rotates light to the right (clockwise)
Define levorotatory
(-)
isomer rotates light to the left (counterclockwise)
Dextrorotary and levorortatory tell you what?
light rotations
NOTHING about chemical structure
Define enantiomers
One of two steroisomers that are non-superimposable mirror images of each other
- Can have large differences in potency, receptor fit, activity, etc
Change in one position (1 is R, 1 is S)
Define eutomer
Most active isomer delivering the desired activity
Define diastereomers
Molecules that are non-superimposable AND non-mirror images due to containing more than one chiral carbon
- Different physicochemical properties –> different biological activities
Define racemates
A mixture of the two left and right handed optical isomers in equal amounts (R and S)
- Chemical synthesis or in vitro
What is ibuprofen
NSAID
Sold as a racemate of R and S forms
S acts within 15 minutes and has 50% reduced side effects than the R isomer
What is the International Union of Pure & Applied Chemistry (IUPAC) name?
The chemical name of the active pharmaceutical ingredient compound
- Leaves no room for ambiguity
- Often too long to mess with
What is the International Nonproprietary Name (INN) or generic name?
US Adopted Name used to ID the same active pharmaceutical ingredient over a number of products
What is the brand name?
Owned by the producing company
