Lecture 15 Flashcards
Chirality
Natural Systems + Chirality
- Most biological molecules are found in only one specific steroisomer
- Most carbs are D-series
- Most amino acids are L-series
- Usually one enantiomer is active while the other is not
Chirality + Drug Targets
- Three-point interactive
- Agonist/substrate with receptor/enzyme site respectively
Thalidomide
- S -Safe/effective form
- R, form it was sold in that caused birth defects
- Example of chirality, drug was withdrawn
Chirality + Drugs
- Most medicinal agents occur in a single, optically active, isomer form
- Half of drugs available are chiral
- Only one enantiomer has a beneficial effect while the other can be harmful in some cases
Chirality _+ Absorption
Methotrexate, the L enantiomer of the drug are actively absorbed while the D- form absorbed in the intestine by passive diffusion.
Distribution + Chirality
The S enantiomer of propranolol is selectively bound in heart, whilst the R isomer is selectively incorporated into the adipose tissue.
Metabolism + Chirality
R enantiomer of warfarin has longer elimination half life. S-warfarin is metabolized by CYP 2C9, R-warfarin is metabolized by CYP 1A2, 2C19 and 3A4.
Excretion + Chirality
Renal clearance of plasma Quinidine is four times greater than quinine, its diastereoisomer
Chiral History
- During the “Golden Age” of drug discovery & development, the 1950s to the 1970s, stereochemistry was largely ignored resulting in approximately 25% of pharmaceuticals being marketed as racemates by the 1980s.
- Advances in chemical technology associated with synthesis, analysis and preparative scale separation of chiral molecules resulted in a change in philosophy with respect to drugs.
- Facilitated the pharmacological evaluation of single stereoisomers; increasing concern with respect to safety issues; Regulatory interes
Chiral Costs
- 2006, 80% of small-molecule drugs approved by the FDA were chiral
- 75% were single enantiomers
- The field of asymmetric synthesis is expanding rapidly, 50% of chiral drugs use chiral technologies
- Due to FDA policy, decision to create racemic mixture must be justified in quality, safety, and efficacy, may be case-by-case
Stereoisomers
-Same constitutional isomer, difference in the way they are arranged in 3D space at one or more atoms.
Enantiomer
Compounds that are non-super-imposable mirror images of each other.
Achirl
Molecule or object that is superimposable on its mirror image.
Stereocenter
- Atom, or group of atoms, that can potentially cause a molecule to be chiral.
- Most common example is carbon
- Quaternary and tertiary nitrogens in junction with bicyclic rings, hypervalent phosphorous (3+ bonds), and hypervalent sulfurs (2+ bonds) can also be chiral, but are unusual
Stereogenic Sulfur
Sulfur that is is chiral by its fourth bond being a pair of electrons. EX: Omeprazole
