Kunze: Sterochemistry Flashcards
1
Q
Stereoisomers
A
- Different stereoisomers have different ADME and therapeutic properties
- Different biological response, side effects, protein binding, and pharmacokinetics
- Single isomers are encouraged for drugs today
- FDA now requires that the properties of stereoisomers of drugs that are intended to be given as a isomeric mixture to be determined separately whenever possible
2
Q
Stereospecific vs. Stereo-selective
A
- Stereospecific: has property that other isomer doesn’t
- Stereo-selective: same biological properties but different magnitudes of effect
3
Q
Chiral Centers: Enantiomers
A
- When there is one chiral center in the molecules, the two possible isomers are called enantiomers
- Racemate/racemic mixture is 50:50 mixture of two isomers
4
Q
Cahn-Ingold-Prelog Rules for Assigning R and S
A
- Higher atomic number, higher priority
- Keeping moving out and comparing atom by atom
- Double bonds are like being bound to two of the same atom
- R is clockwise, S is counter clockwise if spinning 1,2,3 and H in the back of plane
5
Q
Warfarin Stereochemistry Example:
A
- pKa=5; Log P=3.5
- One chiral center
- Given as racemate and has a low TI needing individualized dosing
- Sensitive to CYP2C9 interactions
- Steroselective inhibition of Vitamin K epoxide reductase
- S is 3 fold more potent than R based on dose
- Half-life of S is 24 hours, Half-life of R is 45 hours
- Single isomer development failed to improve outcomes
6
Q
Fluoxetine sterochemistry example
A
- pKa=9; Log P=3.5
- Wavy line to show chiral center
- Only SSRI approved in pregnancy
- N-demethylated metabolite concentrations exceed parent at multiple dosing due to extremely long half-lives
- Metabolites are pharmacologically active and stereoselectively inhibit metabolism of parent isomers
- Parent/metabolites are potent inhibitors of CYP2D6 and CYP2C9
- Parent/metabolites accumulate with repeat dosing
- Efforts to develop enantiomers failed
7
Q
Ofloxacin (fluoroquinone antibiotic, topoisomerase inhibitor)
A
- S (levaquin) more active than R; S lowers risk of tendon rupture
- Multiple ionizable groups; zwitterionic; good bioavailability (>95%) because active transporters
8
Q
Omeprazole:
A
- Sulfur chiral center
- Lowest priority group is the lone electron pair that does not undergo racemization
- Polymorphic metabolism by CYP2C19
- S (Nexium) provides better AUC and less individual variability
- Some PK stereoselectiviety
- Debate whether Nexium is worth the cost
- PPI unstable in stomach acid, coated for release in the intestine
- Irreversible inhibitors of the proton pump
9
Q
Ibuprofen
A
- S enantiomer is the active form (Stereospecific)
- Efforts to develop the single enantiomer to improve potency were discontinued when it was realized that acyl-CoA recemase converted R to S
- During racemization the proton is lost
10
Q
Multiple Chiral Centers (Diastereomers)
A
- Total number of isomers is 2n where n is # of chiral centers
- When both stereocenters are inverted, enantiomers
- When one stereocenter is inverted, diastereomers
- Enantiomers are similar whereas diastereomers are quite different
- Multiple chiral centers are common in steroid and drugs that bind to enzyme or receptors of peptides
- “Natural” amino acid stereochemistry is often required
11
Q
Things to expect or worry about when isomeric drugs are compared
A
- Different ADME properties because transporter, metabolic enzyme and albumin may interact stereoselectively or stereospecifically
- Different pharmacology at receptors
- Different off-target effects and side effects
- Racemization of stereocenters sometimes occur obviated the need for single isomers
- Drug companies often do a follow-up on racemic mixture drugs. Racemate goes generic first. Follow up isomer needs to be different enough to:
- Warrant separate patents
- Provide a health benefit over other products on the market
- Be cost effective
- Formulary boards often determine whether the new drug is cost effective…putting pharmacists right in the middle of it
12
Q
Enzymes as Targets
A
- Many drugs inhibit enzymes
- These drugs are often structurally similar to endogenous substrate
- Most inhibitors are competitive and bind reversibly
- Try and design drugs with increased affinity (lower IC50) and fewer off target effects
13
Q
Reversible Inhibitors: Example; Statin Drugs and HMG CoA Reductase
A
- Reductive cleavage of HMG-CoA to Mevalonic Acid
- Rate limiting step in cholesterol production
- Decrease LDL and increase HDL
- Statins
- Reversible
- Tight binding (IC50 in low nM)
- Competitive
- Enter cell to do job
- Only occupy a portion of the binding site for HMG CoA
14
Q
Lipitor
A
- Highly lipophilic drug
- pKa=4.5; uncharged at low pH; will be absorbed in the duodenum
- Poor bioavailability; metabolizing enzyme in enterocytes and liver
- Major target for drug exists in the liver
- Only 15% of drug gets past 1st pass metabolism
- Metabolized by CYP3A4; lots of variation in the population
- Ortho-para hydroxylation and then glucoronidation
- When Lipitor given orally 30% pharmacology effect from drug itself, rest is from metabolites
15
Q
Different Types of Statins
A
- Red portion is highly conserved that mimics the cleaved off end of HMG-CoA
- Type 2 statins are more potent and need less dosing
