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
16
Q
The structures of some of the common statins are similar to each other
A
- CoA part of HMC CoA lies outside of binding area for statins
- Rigid core of statin bind to enzyme in similar configuration and expand the active site
- Binds to active site similarly and then add lipophilic groups that are powerful binders and inhibitors of the enzyme
- Type 2 have para fluoro phenyl group which associates with an arginine side chain
- This ring must bind orthogonal to the ridged core
17
Q
Type 2 and Type 1 Statins differ in ring closing
A
- Type 2 is a lactone
- Ring has to be open for it to bind to the enzyme
- Ester hydrolysis easily opens up ring in Type 1 in the stomach
18
Q
Irreversible Inhibitors: Acetylcholine Esterase and Sarin
A
- Ach is quaternary ammonia compound that is always charged
- Nicotinic and muscarinic receptors
- Cholinergic nerve transmission is modified by a wide range of drugs
- Cholinergic side effects are common
- Intensity and duration of action is determined by esterase on post-synaptic membrane (ACHE)
- Many things inhibit this enzyme; potentiates cholinergic effect
- Neostigmine is a reversible inhibitor of ACHE and a substrate for enzyme
- Sarin is an irreversible inhibitor that phosphorylates the active site serine
19
Q
Acetylcholine esterase:
A
- Acetic acid and choline are made
- Drugs bind to ACHE esterase and stop the reaction
20
Q
Neostigmine
A
- Pseudo-irreversible reaction because it is REALLY slow
21
Q
Sarin
A
- Funny chiral center with P. The P doesn’t undergo interconversion.
- Irreversible
- Treat with Ach mimic antagonist (atropine); we can reverse some of the effects
22
Q
Extracellular receptors as targets
A
- Muscarine is a quartenary nitrogen; always positively charged
- Doesn’t cross membrane easily
- Expect 8 isomers
- Nicotine has two basic ionizable groups (pyridine pKa ~5, alkylamine pKa~9)
- Charged at physiological pH
23
Q
Muscarinic Receptors
A
- Type of Action
- All G coupled receptors
- M1,3, and 5 control intracellular calcium via PIP2
- M2, and 4 inhibits cAMP
- Agonist
- Methanocholine
- Diagnostic for bronchial hypersensitivity in asthma
- (S) enantiomer more potent
- Antagonist
- Atropine
- Classic antagonist
- S is 120 times more potent
24
Q
Nicotinic Receptors
A
- Type of action:
- Na/Ca channel
- Multiple subtypes
- Agonist
- Chantix; smoking cessation; bizarre behavior
- Antagonist
- Succinyl Choline
- Depolarizing neuromuscular blocking agent
- Break in half and get 2 acetylcholines
