The Organic Chemistry of Drug Design and Drug Action - PowerPoint PPT Presentation

1 / 63
About This Presentation
Title:

The Organic Chemistry of Drug Design and Drug Action

Description:

The Organic Chemistry of Drug Design and Drug Action Chapter 7 Drug Metabolism Glutathione Conjugation Scheme 7.50 Further Metabolism of GSH Conjugates Metabolism of ... – PowerPoint PPT presentation

Number of Views:829
Avg rating:3.0/5.0
Slides: 64
Provided by: tryptopha
Category:

less

Transcript and Presenter's Notes

Title: The Organic Chemistry of Drug Design and Drug Action


1
Oxidative O-Dealkylation
analgesic O-Demethylation is rapid
2
Regioselective O-Demethylation
In dogs O-demethylation only here
blood pressure maintenance
3
Oxidation on the Carbon Next to a Lactone Oxygen
Scheme 7.34
4
Oxidations of Carbon-Sulfur Systems
Three principal biotransformations Oxidative
S-dealkylation, desulfuration, and S-oxidation
Oxidative S-dealkylation
sedative
5
Desulfuration (CS ? CO)
6
S-Oxidation
Scheme 7.35
Occurs with P450 and flavin monooxygenase Flavin
monooxygenase gives sulfoxides only P450 gives
both S-dealkylation and sulfoxides
7
antihelmintic agent
Gives both S-dealkylation and S-oxidation
metabolites
8
Thiophenes are converted to thiophene S-oxides,
which are electrophilic and can bind to liver
proteins.
Scheme 7.36
added in vitro to mimic a liver protein cysteine
residue
9
Oxidation of Sulfoxide to Sulfone
Oxisuran, an immunosupressive drug, is oxidized
to the sulfone
10
Other Oxidative Reactions
Oxidative Dehalogenation
Scheme 7.37
volatile anesthetic
11
Oxidative Aromatization
12
Oxidation of Alcohols to Aldehydes and Aldehydes
to Carboxylic Acids
Scheme 7.38
Oxidation of an aldehyde to a carboxylic acid is
generally faster than reduction of an aldehyde to
an alcohol. Cytochrome P450 also oxidizes
alcohols to aldehydes and aldehydes to carboxylic
acids.
13
Oxidation of an Alcohol to a Carboxylic Acid by
NAD Enzymes
anti-AIDS drug
14
Oxidation of an Alcohol to a Carboxylic Acid by a
P450 Isozyme
antihypertensive drug
The metabolite is 10 times more potent an
antagonist of the angiotensin II receptor than
losartan.
15
Reductive Reactions
Table 7.6
16
Carbonyl Reduction
Typically aldo-keto reductases that require NADPH
or NADH
When the racemic mixture was administered, the
R-isomer gave aromatic hydroxylation (both 6-
and 7-hydroxyl) as the major metabolites.
Administration of racemates can affect the
metabolism of each enantiomer.
17
Species Variation in Stereochemistry
opioid antagonist used for addiction
rehabilitation
6a-alcohol (7.102, R1 OH, R2 H) in
chickens 6b-alcohol (7.102, R1 H, R2 OH) in
rabbits and humans
18
a,b-Unsaturated Ketone Double Bonds Reduced
The double bond of norgestrel (7.94, R3 Et) and
norethindrone (7.94, R3 Me) is reduced
norgestrel gives 3a-alcohol (R1 H, R2 OH) but
norethindrone gives 3b-alcohol (R1 OH, R2 H).
Double bond reduced
19
Nitro Reduction
Scheme 7.39
20
Nitro Reduction
Often the amine metabolite is not observed
because it is easily air oxidized back to the
nitro compound, for example, the anti-parasitic
agent niridazole is reduced to the hydroxylamine,
but is reoxidized to niridazole.
21
Azo Reduction
Scheme 7.41
22
Azo Reduction
Scheme 7.42
Reduction carried out by intestinal bacteria.
23
Reduction of Azido to Amino
Anti-AIDS
24
3? Amine Oxide Reduction
imipramine N-oxide Reduced in the presence of O2
to the amine
25
Reductive Dehalogenation
Scheme 7.43
Cytochrome P450 in the absence of O2
May be the cause for Halothane hepatitis
26
Carboxylation Reactions
Metabolized to 7.121, R COOH
27
Hydrolytic Reactions
(nonspecific esterases and amidases in plasma,
liver, kidney, and intestines)
Electron-withdrawing groups accelerate
hydrolysis. Conjugation with carbonyls
decelerates hydrolysis. Steric hindrance
decelerates hydrolysis.
Hydrolyzed by all human tissues
28
Selectivity for Aliphatic vs. Aromatic Esters
Some esterases catalyze the hydrolysis of
aliphatic esters and others aromatic esters.
In vivo hydrolysis
Hydrolysis by liver enzymes in vitro
29
Amide vs. Ester Hydrolysis
Generally amides are more slowly hydrolyzed than
esters.
Hydrolysis of procaine gtgt procainamide
30
Amide vs. Ester Hydrolysis
No amide hydrolysis
Ester hydrolysis only
31
Some amides are hydrolyzed at rates comparable to
that of esters (maybe because of
electron-withdrawing groups).
32
Amide Hydrolysis - Enantiomer Toxicity
Both enantiomers are anesthetics (R)-isomer ?
causes methemoglobinemia (S)-isomer not
hydrolyzed
33
Enantiomer-Selective Hydrolysis
The (R)-(-)-ester is hydrolyzed in the liver, but
the (S)-()-ester is hydrolyzed in the brain.
34
Differential Enantiomeric Metabolism
Scheme 7.44
35
Phase II TransformationsConjugation Reactions
Attachment of small polar endogenous molecules to
drugs or (more often) to metabolites of phase I
enzymes Further deactivates drugs and produces
water-soluble metabolites readily
excreted Conjugation reactions take place with
hydroxyl, carboxyl, amino, heterocyclic N, and
thiol groups if not present, a phase I reaction
introduces it Many drugs are excreted without any
modification at all.
36
Mammalian Phase II Transformations
Table 7.7
37
Glucuronidation
Biosynthesis and Reactions of UDP-glucuronic Acid
Scheme 7.45
38
Classes of Compounds Forming Glucuronides
Table 7.8
39
Diseases (inborn errors of metabolism) associated
with defective glucuronidation
  • Crigler-Najjar syndrome and Gilberts disease
  • deficiency of UDP-glucuronosyltransferase
  • adverse effects caused by accumulation of drugs
  • inability of neonates to conjugate the
    antibacterial chloramphenicol (7.138) - gray
    baby syndrome)

40
Species Specificity, Regioselectivity, and
Stereoselectivity
Antibacterial drug sulfadimethoxine is
glucuronidated in humans (at arrow) but not in
rats, guinea pigs, or rabbits.
Sulfadimethoxine
41
Two different glucuronides are formed
here
here
The R,R-(-)-isomer is conjugated with higher
affinity, but lower velocity than is the
S,S-()-isomer.
42
The two hydroxylated isomers of nortriptyline
metabolite 7.140 (R OH) are glucuronidated
stereospecifically. Liver and kidney
glucuronosyltransferases convert only the
E-()-isomer and the intestinal enzyme converts
only the (E)-(-)-isomer.
43
Sulfate Conjugation
Occurs less often than glucuronidation (limited
availability of SO4). Main substrates are
phenols, but also aliphatic OH, amines, and
thiols (much less).
Scheme 7.46
44
Glucuronidation and sulfation can occur on the
same substrates, but the Km for sulfation is
usually lower, so it predominates.
sulfation here (phenolic OH instead of aliphatic
OH)
bronchodilator
45
Hepatotoxicity and Carcinogenicity by Sulfation
Scheme 7.47
46
Amino Acid Conjugation
Scheme 7.48
Glycine conjugates are most common in
animals. L-Glutamine conjugates are most common
in primates (insignificant in nonprimates).
47
Metabolism of Brompheniramine (antihistamine)
Scheme 7.49
48
Glutathione Conjugation
Glutathione GSH
Found in all mammalian tissues (5-10 mM in liver
and kidneys) Scavenger of harmful electrophiles
49
Glutathione Conjugation
Scheme 7.50
50
Further Metabolism of GSH Conjugates
Metabolism of glutathione conjugates to
N-acetyl-L-cysteine conjugates
Scheme 7.51
Referred to as phase III metabolism
51
Water Conjugation
Epoxide hydrolase reactions such as hydrolysis
of arene oxides, as discussed earlier.
52
Acetyl Conjugation
Important for xenobiotics with primary NH2
Converts ionized amine (RNH3) to uncharged amide
  • Metabolites are less water soluble possibly
    serves the function of deactivating the drug.
  • Occurs widely in animals
  • Extent of N-acetylation in humans is a
    genetically determined characteristic - called
    acetylation polymorphism.
  • Egyptians are slow acetylators - toxic buildup
    of drugs but longer drug effectiveness.
  • East Asians and Canadian Eskimos are fast
    acetylators - inadequate response.

53
Examples of Drugs Exhibiting Acetylation
Polymorphism
Antibacterial
Antituberculosis
Treatment of leprosy
54
Acetylation of Amines
Scheme 7.52
Makes less polar RNH3 ?
55
Fatty Acid and Cholesterol Conjugation
Fatty acid metabolites of 7.174 deposit in liver,
spleen, adipose tissue, and bone marrow.
Flashbacks by habitual cannabinoid users after
they
stop using the drug may be from the lipophilic
conjugates retained in tissues that are converted
back to the cannabinoid.
Development of the hypolipidemic drug 7.176 had
to be stopped because cholesterol esters
deposited in the liver.
56
Methylation - relatively minor in drug metabolism
Generally occurs when the compound has a
structural similarity to normal endogenous
substrates of the methyltransferase.
Scheme 7.53
57
Methylated here regiospecifically
bronchodilator
Methylation by catechol O-methyltransferase
requires a catechol (an aromatic 1,2-dihydroxy)
substrate. An aromatic 1,3-dihydroxy compound
(7.181) does not get methylated.
58
Phenolic hydroxyls also can get methylated
Methylation here
(minor)
59
N-Methylation also occurs to a minor extent.
Oxyprenolol is N-dealkylated to 7.183, R H,
which is methylated to 7.183, R CH3.
antihypertensive
60
S-Methylation
Captopril is S-methylated.
61
Hard and Soft Drugs
Sometimes a drug is not metabolized rapidly
enough (long plasma half life). The plasma half
life for an analog (7.188) of the antiarthritis
drug celecoxib (7.187) in dogs is about a month!
To shorten the plasma half life the para-chloro
was changed to para-methyl because a carbon next
to an aromatic group is known to undergo P450
oxygenation.
plasma t1/2 9 h
plasma t1/2 680 h
62
Compounds (like 7.188) that are difficult to
metabolize are termed hard drugs. Those that are
easily metabolized (like 7.187) are soft drugs
(also called antedrugs). Soft drugs are designed
to have a predictable and controllable metabolism
to nontoxic and inactive products after they have
achieved their pharmacological effect.
63
Retro Approach Related to Soft Drugs
Identify a biologically inactive metabolite, then
modify to an active drug in such a way that this
modification is known to be reversed to the
inactive metabolite. The anti-inflammatory agent
loteprednol etabonate (7.191) was designed based
on the known inactive steroid 7.193 an analog of
the anti-inflammatory drug prednisolone (7.192).
Compound 7.191 is metabolized by esterases to
7.193 after it elicits its anti-inflammatory
effect.
Write a Comment
User Comments (0)
About PowerShow.com