SAR Antidiabetic Agents

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SARAntidiabetic Agents
X O, S, or N
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SARDiuretics (2 types)
hydrochlorothiazides R2 is an electrophilic group
high ceiling type
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(No Transcript)
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somatostatin agonist
scaffold peptidomimetic
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Ionic Interaction
Basic groups, e.g., His, Lys, Arg
(cationic) Acidic groups, e.g., Asp, Glu
(anionic)
Figure 3.1 ?G -5 kcal/mol
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Hydrogen Bonding
Type of dipole-dipole interaction between H on
X-H (X is an electronegative atom) and N, O, or F
?G -3 to -5 kcal/mol
Figure 3.3
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Conformationally rigid analog(ring-chain
transformation)
Less potent therefore flexibility is important
Need to separate agonist and antagonist
properties - structures too similar to histamine.
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Consider pharmacodynamics
Imidazole ring can exist in 3 forms
Figure 3.25
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Hammett Study of Electronic Effect of Side Chain
favored for R e- -withdrawing
favored for R e- -donating
pKa of imidazole 6.80 pKa of imidazole in
histamine 5.90 Therefore, side chain is e-
-withdrawing, favoring 3.72a.
pKa of imidazole in burimamide 7.25 Therefore,
side chain is e- -donating, favoring 3.72c.
Need to make side chain e- -withdrawing.
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PLP
PLP bound at active site
abbreviated structure
Figure 4.5
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First Step in All PLP-Dependent Reactions
Scheme 4.14
From here all of the PLP reactions occur
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PLP Racemases
Scheme 4.15
All steps are reversible Keq 1
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Decarboxylases
Scheme 4.16
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First Half Reaction of Aminotransferases
Scheme 4.18
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Second Half Reaction of Aminotransferases
Scheme 4.19
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?-Elimination
When X is a leaving group, elimination can occur.
Scheme 4.20
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The carbon atom that is transferred is derived
from serine in a PLP-dependent ?-cleavage
reaction.
atom to be transferred
Scheme 4.22
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N5 ,N10-Methylenetetrahydrofolate can be oxidized
by a NADP-dependent enzyme to give N5
,N10-methylenyltetrahydrofolate.
Scheme 4.24
hydrolysis gives
N10-formyltetrahydrofolate
N5-formyltetrahydrofolate
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Mechanism for P450-Catalyzed Hydroxylation
Scheme 4.35
high-energy iron-oxo species
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Some General P450 Mechanisms
Hydroxylation
Scheme 4.36
radical lifetime is very short
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Epoxidation
Scheme 4.37
Sulfoxidation
Scheme 4.38
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Mechanism of Action
Function of Zn cofactor
Figure 5.5
May be similar to carboxypeptidase A, another
Zn-dependent peptidase.
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Binding of Enalaprilat to ACE
Figure 5.9
additional binding interactions
enalaprilat
Poorly absorbed orally - remedied by using ethyl
ester (at arrow) (enalapril) which is hydrolyzed
by esterases to give enalaprilat (a prodrug).
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Hypothetical Mechanism of Adenosine Deaminase
Scheme 5.8
pentostatin mimics this
2?-deoxyadenosine
2?-deoxyinosine
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Multisubstrate Analog N-Phosphonoacetyl-L-Asp
(PALA)
Aspartate transcarbamylase - de novo biosynthesis
of pyrimidines
Scheme 5.9
carbamoyl phosphate
isostere - no longer a leaving group, mimics
phosphate
N-carbamoyl-L-Asp
PALA
Tumor resistance

• tumor cells acquired ability to utilize
  preformed circulating pyrimidine nucleosides
• increased carbamoyl phosphate
• increased aspartate transcarbamylase

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Aspirin causes specific acetylation of active
site Ser-530.
Scheme 5.17
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Mechanism of Aminotransferases
Scheme 4.18
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Mechanism of Inactivation of GABA-AT by Vigabatrin
Scheme 5.21
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vigabatrin
70
Michael addition
electrophile
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Mechanism of Decarboxylases
Scheme 4.16
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Product-Derived Mechanism-Based Inactivator
?-difluoromethyl putrescine
Scheme 5.25
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Proposed Mechanism of MAO B by Selegiline
selegiline
Scheme 5.27
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Mechanism of Thymidylate Synthase
Scheme 5.29
dihydrofolate reductase
tetrahydrofolate
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Mechanism of Inactivation of Thymidylate Synthase
by 5-Fluoro-2?-deoxyuridylate
Scheme 5.30
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The nitrogen atom is conjugated with the
cyclohexadienone which lowers the reactivity.
Scheme 6.6
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Heme-dependent Mixed Function Oxidase
Scheme 4.35
Oxidizing agent
Reducing agent
Activated coenzyme
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Mechanism for Arene Oxide Formation and Aromatic
Hydroxylation
(favored over a)
Scheme 7.4
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Rearrangement of Arene Oxide to Arenol
Scheme 7.6
Called the NIH shift
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Competing with the NIH Shift
Scheme 7.7
deprotonation
The more stabilized the carbocation intermediate,
the less favored is a for hydride shift - more
deprotonation.
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NIH Shift with Groups Other than H
Scheme 7.8
p-chloroamphetamine
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Toxic Product of Alkene Oxygenation
Scheme 7.14
aflatoxin B1
DNA adduct
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Reductive Reactions
Table 7.6
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Reductive Dehalogenation
Scheme 7.43
Cytochrome P450 in the absence of O2
May be the cause for Halothane hepatitis