SARAntidiabetic Agents

X = O, S, or N

2.33

R SO2NHCHN

XR'

SARDiuretics (2 types)

hydrochlorothiazides

R2 is an electrophilic group

high ceiling type

2.34

SNH

N

NH2SO2 O O

R2R1

2.35

R2

R1NHSO2 CO2H

X

10. Azomethine

11. Pyridine

12. Benzene

13. Ring equivalents

14. Spacer group

15. Hydrogen

N C

CN

NNO2

N+

R NR3+

N N

N S

N

S O

NO

N

O

N

HN

R NO R' N

O R'

RR

R

HN O

OH3C

R

O

N

NH

R

H

NH2

(CH2)3

H F

somatostatin agonist scaffold peptidomimetic

O

OO

O O

NH

NH2

NH

NH2

HN

NH

O

N

O

NH

ON

O

NH

OO

H

OH

2.70 2.71

Ionic Interaction

Basic groups, e.g., His, Lys, Arg (cationic)

Acidic groups, e.g., Asp, Glu (anionic)

Figure 3.1 G° ≈ -5 kcal/mol

O

NH

O

O

NH

NH2

H2Npivagabine

Hydrogen Bonding

Type of dipole-dipole interaction between H on X-H (X is an electronegative atom) and N, O, or F

Figure 3.3G° ≈ -3 to -5 kcal/mol

intramolecular

intermolecular

O

O

O

H

H :OH

Conformationally rigid analog(ring-chain transformation)

Less potent; therefore flexibility is important

Need to separate agonist and antagonist properties - structures too similar to histamine.

+

3.69

HN N NH

S NH2

Consider pharmacodynamics

Imidazole ring can exist in 3 forms

Figure 3.25

+

3.72a 3.72b 3.72c

HN N HN NH N NH

RRR

Hammett Study of Electronic Effect of Side Chain

favored forR = e- -withdrawing

favored forR = 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.

+

3.72a 3.72b 3.72c

HN N HN NH N NH

RRR

PLP

Figure 4.5

PLP bound at active site

abbreviated structure

+

+

4.19a

4.19b

+

+N

O-

HN+

CH3

H

OP

O

O-

-O

H

Lys

BNH

OH

NH+

Lys

=O3POH

N

OH

CH3

OH=O3PO

First Step in All PLP-Dependent Reactions

From here all of the PLP reactions occur

Scheme 4.14

+

..

4.21

..

+

..

+

4.20

NH2 COO-

R

N

O

NHN

LysH

R

COO-

B+

H:B

N

NH2N

+BHLysR

COO-

:B

N

N

+BHLys

R COO-NH2

:B

O

O

=O3PO

=O3PO=O3PO

O3PO

CH3

O

N

N

Lys

H

__

+

H

H

BH

BH

BH

BH

H

PLP Racemases

All steps are reversible

Keq = 1

Scheme 4.15

E•P

E•S

See Scheme 4.14

..

E + P

E + S

:NH2COO-

H

R

:B

B+

H

N+

NH

O

N

Lys

RH

-OOC

H

B:

B+

HLys

:N

NH

O

H2N+

RH

-OOC

H2N

R

H

COO-

=O3PO =O3PO

H

BH+

=O3PO O

NH

N

Lys

H

NH

N

RCOO-

O=O3PO

H

H

NH

N

R COO-

O=O3PO

H

NH

N

R COO-

O=O3PO

H

NH

N

R COO-

O=O3PO

H

NH

N

R COO-

O=O3PO

H

H

Lys

NH2..

=O3PO O

NH

N

Lys

H

H H

..

DecarboxylasesScheme 4.16

See Scheme 4.15

irreversible

-CO2

+

See Scheme 4.14

+B

H

Lys

NH2 H

NH2

RH

:NH2COO-

H

R

=O3PO O

NH

N

Lys

H

+NH

HR

CO

-O

=O3POO

HN

NH

=O3POO

HN

NH

HR

=O3POO

HN

..

+NH

HR

=O3POO

HN

+NH

HR

=O3POO

HN

+NH

HR

=O3POO

HN

HLys

First Half Reaction of Aminotransferases

Scheme 4.18

See Scheme 4.14

4.26b

4.27

H215N

COO-

H

R

R

-OOCO

4.26c 4.26a

13

13

4.28

=O3PO O

NH

N

Lys

H

NH

15N

R-OOC

O=O3PO

H

NH

15N

RCOO-

O=O3PO

H

H 13

:B

13

NH

15N

R-OOC

O=O3PO

H

13

+B

H

NH

15N

R-OOC

O=O3PO

H

13

NH

15N

R-OOC

O=O3PO

H

13

O H

H

:B

NH

15N

O=O3PO

H

NH

15N

O=O3PO

H:

-OOC OHR +B

H

NH

15NH

O=O3PO

H

RO-OOC H :B

13

:

13

:

H

Second Half Reaction of Aminotransferases

Scheme 4.19See Scheme 4.15

18R'

-OOCO

+B

H

:B+B

H

15NH2

R'COO-

H

Lys

NH2

NH

15N

O=O3PO

H

-OOC 18OHR'

+ H

NH

15N

O=O3PO

H:

NH

15N

O=O3PO

H

-OOC 18OHR'

..

NH

15N

O=O3PO

H

-OOC R'

H

:B

NH

15N

O=O3PO

H

-OOC R'

..NH

15N

O=O3PO

H

-OOC R'

NH

15N

O=O3PO

H

-OOC R'

+B

H

NH

15N

O=O3PO

H

COO-

R'H

NH

+N

O=O3PO

H

Lys

H

-H218O

-Elimination

When X is a leaving group, elimination can occur.

Scheme 4.20

See Scheme 4.14

See Scheme 4.15

+ NH4+

:NH2COO-

H

X

Lys

:NH2-OOC

NH2

-OOC

O

NH

N+

O=O3PO

H

COO-H

:B

X

NH

+N

O=O3PO

H

X-OOC

NH

+N

O=O3PO

H

X-OOC

NH

+N

O=O3PO

H

X-OOC

NH

+N

O=O3PO

H

-OOC

NH

+N

O=O3PO

H

Lys

NH

+N

O=O3PO

H

Lys

-X-

H2O

The carbon atom that is transferred is derived from serine in a PLP-dependent -cleavage reaction.

atom to be transferred

Scheme 4.22

See Scheme 4.15

See Scheme 4.14

:NH2COO-

H

OH

O CH2+B

H

Lys

:NH2H2N COO-

4.35

NH

+N

O=O3PO

H

Lys

NH

+N

O=O3PO

H

*OH:B

COO-H

NH

+N

O=O3PO

H

COO-

..

H

NH

N+

O=O3PO

H

COO-H

NH

+N

O=O3PO

H

COO-H

NH

+N

O=O3PO

H

COO-H

H

NH

+N

O=O3PO

H

Lys

*

*

N5 ,N10-Methylenetetrahydrofolate can be oxidized by a NADP+-

dependent enzyme to give N5 ,N10-methylenyltetrahydrofolate.

Scheme 4.24

hydrolysis gives

N10-formyltetrahydrofolateN5-formyltetrahydrofolate

b

+

+..

4.40

a

b

a

4.424.41

NN

NHNH2N

HO NR'H

H

N

NH2

O

N

R

NR'

H

HO

H2NHNN

N

NN

NHNH2N

HO NR'

H O

:B

HO H

N

R

O

NH2

HH

H

:B

B+H

+BH

NR'HO

H2NHN

NH

N

N

H OH

N

N

N

HNH2N

HO NHR'

O

* *

* **

4.43

Mechanism for P450-Catalyzed HydroxylationScheme 4.35

high-energy iron-oxo species

S

FeIII

ON

N N

N

HH

S

FeIII

N N

N N

S

FeII

N N

N N

S

FeIII

ON

N N

N

O

S

FeIII

ON

N N

N

O

S

FeIII

ON

N N

N

OH

S

FeIII

ON

N N

N

S

FeVN

N N

N

S

FeIVN

N N

N

OO

S

FeIV

ON

N N

N

B H

H B

4.60

4.61d

NAD(P)H

FMN

FMN

:

4.61a4.61c

NAD(P)+

:: : :

4.61b

: : : R-H

FMN

FMN

FAD

R-H

FMNH

-H2O

FADH

O2

R-O-H

R-H R-H R-H R-H

R-H

Some General P450 MechanismsHydroxylation

radical lifetime is very short

Scheme 4.36

H C R'

R

R''

HO C R'

R

R''

S

FeIV

ON

N N

N

C R'

R

R''

S

FeIV

OH

N

N N

N

S

FeIII

N N

N Nrebound

: :

oxygen

4.61b 4.62

Sulfoxidation

EpoxidationScheme 4.37

Scheme 4.38

S

FeIV

ON

N N

N

S

FeIV

O

N

N N

N

S

FeIII

N N

N N

R'R R R' R'R

O:

4.63

rebound

:

oxygen

RS

R'

S

FeIV

ON

N N

N

RS

R'

S

FeIV

O

N

N N

N

RS

R'

S

FeIII

N N

N N

:O:: ..

rebound

: :..

oxygen

:

Mechanism of Action

Function of Zn++ cofactor

Figure 5.5

May be similar to carboxypeptidase A, another Zn++-dependent peptidase.

NH CH

R2

C

O

NH CH

R1

C

O

NH CH

R1'

C

OHN CH

R2'

COO-

Zn++

-OH

Binding of Enalaprilat to ACE

additional binding interactions

enalaprilat

Figure 5.9

Poorly absorbed orally - remedied by using ethyl ester (at arrow) (enalapril) which is hydrolyzed by esterases to give enalaprilat (a prodrug).

NH CH

CH2

C

O

NH CH

CH3

C

O

N CH CO

O

H

B

CH2

CO

OCHN

O

CH

CH3

NH2CO

OCHNH

CH2

CO

O

CHNC

O

CH

CH3

NHCH

C

CH2

O O

substrate

products

5.28(R = PhCH2CH2R' = __)

S1' S2'ZnII

S1

Hypothetical Mechanism of Adenosine Deaminasepentostatin mimics this

2-deoxyinosine

2-deoxyadenosine

Scheme 5.8

5.62

5.615.59

N

N

H2N

N

N

OHO

OH

OH

HON

O

N

N

N

H

OH295Asp

O

O

Zn2+

H217Glu

O

O

296Asp

OO

H

5.60

N

N

NH2

N

N

OHO

OH

H

O

H295AspO

O

Zn2+

H217Glu

O

O

296Asp

OO

H

N

N

NH2

N

N

OHO

OH

O

295AspO

O

Zn2+

H217Glu

O

O

296Asp

OO

HHH

238His

HNNH

238His

N NH

238His

NNH

HH

NH3OH

pentostatin5.58

HN

N N

N

HO H

OHO

OH

Multisubstrate Analog N-Phosphonoacetyl-L-Asp (PALA)

Aspartate transcarbamylase - de novo biosynthesis of pyrimidines

carbamoyl phosphate

isostere - no longer a leaving group, mimics phosphate

N-carbamoyl-L-Asp

PALA

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

Tumor resistance:

Scheme 5.9‡

..

5.67

5.66

O

O

NH2

PO3=

NH2

COO-

H

COO-

COO-

H

COO-

NH2

O

PO3=

NH2

O

COO-

H

COO-

NH

NH2

O

NH

O

CH2

PO3=

COO-

H

COO-

5.65

Aspirin causes specific acetylation of active site Ser-530.

Scheme 5.17

O H

O

H OCH3

O

COO

+O

Tyr-385

H

Tyr-348

O

CH3O

OH

COO

Ser-530

Ser-530

Mechanism of Aminotransferases

Scheme 4.18

See Scheme 4.14

4.26b

4.27

H215N

COO-

H

R

R

-OOCO

4.26c 4.26a

13

13

4.28

=O3PO O

NH

N

Lys

H

NH

15N

R-OOC

O=O3PO

H

NH

15N

RCOO-

O=O3PO

H

H 13

:B

13

NH

15N

R-OOC

O=O3PO

H

13

+B

H

NH

15N

R-OOC

O=O3PO

H

13

NH

15N

R-OOC

O=O3PO

H

13

O H

H

:B

NH

15N

O=O3PO

H

NH

15N

O=O3PO

H:

-OOC OHR +B

H

NH

15NH

O=O3PO

H

RO-OOC H :B

13

:

13

:

H

Mechanism of Inactivation of GABA-AT by Vigabatrin

Scheme 5.21

30%

70%vigabatrin

Michael addition

electrophile

+ PMP

5.116

:

a

b

5.114b 5.114a 5.113

5.115

5.112

5.111

H2N COO-

O

COO-

NH2

COO-

=O3PO O

NH

N

Lys

H

=O3PO O

NH

NH

b

b

a

H

:B

COO-

=O3PO O

NH

NH

a

=O3PO O

NH

NH

..NH2

COO-

=O3PO O

NH

NH+

-OOC

NH2

=O3PO O

NH

NH

COO-

+BH

=O3PO O

NH

NH

=O3PO O

NH

NH

COO-

X -

COO-X

=O3PO O

NH

NH

COO-X

+H2O

Mechanism of Decarboxylases

Scheme 4.16

See Scheme 4.15

irreversible

-CO2

+

See Scheme 4.14

+B

H

Lys

NH2 H

NH2

RH

:NH2COO-

H

R

=O3PO O

NH

N

Lys

H

+NH

HR

CO

-O

=O3POO

HN

NH

=O3POO

HN

NH

HR

=O3POO

HN

..

+NH

HR

=O3POO

HN

+NH

HR

=O3POO

HN

+NH

HR

=O3POO

HN

HLys

Product-Derived Mechanism-Based Inactivator-difluoromethyl putrescine Scheme 5.25

Inactivation as in Scheme 5.24

5.124

5.125H2N

NH2

H CHF2

=O3PO O

NH

N

Lys

H

=O3PO O

NH

NH

CHF2

H2N

HB :

=O3PO O

NH

NH

CHF2H2N

..

=O3PO O

NH

NH

CHF2H2N

=O3PO O

NH

NH

CHH2N

F

F

-F-

Proposed Mechanism of MAO B by Selegiline

Scheme 5.27

selegiline

• •N

N

NH

N O

O

R

S S

O-

ON

R

NNH

N N

NH

N

N

R

O

O-

S

PhN

MePh

N

Me

H :BPh

N

Me

PhN C

Me

Fl

FlH-

PhN

Me

FlH-

Fl

N

NH

N

N

R

O

O-

S

CN

Me

Ph

+H+

N

NH

N

N

R

O

O-

S

NMe

Ph

• •-

-

-

+

:

+

-

5.141 5.142 5.143

5.144

5.1455.146

N

HN

O

O

dRPS

N

HN

O

dRP

S

O

N

NN

HN

NR

H2N

HO

H B

N

NN

HN

NHR

H2N

HO

HN

N

O

O S

dRP

HB

N

HN

O

O S

dRP

N

NNH

HN

NHRH

NH2N

HO

NN

HN

NNHR

H2N

HO

HN

O

dRP

S

O

HN

N

O

CH3

CH3

O

dRPS

5.147

+H+

Mechanism of Thymidylate

Synthase

Scheme 5.29

dihydrofolate reductase

tetrahydrofolate

Mechanism of Inactivation of Thymidylate Synthase by 5-Fluoro-2-deoxyuridylateScheme 5.30

-

-

+

:

5.138 5.148

N

HN

O

O

dRPS

N

HN

O

dRP

S

O

N

NN

HN

NR

H2N

HO

H B

N

NN

HN

NHR

H2N

HO

HN

N

O

O S

dRP

FBF F

The nitrogen atom is conjugated with the cyclohexadienone which lowers the reactivity.

Scheme 6.6

O N

O

R O N

O

R..

Heme-dependent Mixed Function Oxidase

Scheme 4.35Oxidizing

agent

Reducing agent

Activated coenzyme

S

FeIII

ON

N N

N

HH

S

FeIII

N N

N N

S

FeII

N N

N N

S

FeIII

ON

N N

N

O

S

FeIII

ON

N N

N

O

S

FeIII

ON

N N

N

OH

S

FeIII

ON

N N

N

S

FeVN

N N

N

S

FeIVN

N N

N

OO

S

FeIV

ON

N N

N

B H

H B

4.60

4.61d

NAD(P)H

FMN

FMN

:

4.61a4.61c

NAD(P)+

:: : :

4.61b

: : : R-H

FMN

FMN

FAD

R-H

FMNH

-H2O

FADH

O2

R-O-H

R-H R-H R-H R-H

R-H

Mechanism for Arene Oxide Formation and Aromatic Hydroxylation

Scheme 7.4

(favored over a)

RH

R

OH

R

H

HO R

H

O

R

S

FeIV

ON

N N

N

S

FeIV

O

N

N N

N

H

S

FeIII

N N

N N

H

R

S

FeIII

O

N

N N

N

a

a

b

ba

7.15

reboundoxygen

electron

7.16

c

transfer

7.17

7.18

7.19

7.19d

c

c

d

Rearrangement of Arene Oxide to Arenol

Called the NIH shift

Scheme 7.6

+P-450

NADPH

••

H +

-

R

D O

R

H

D

R

O DH

R

O

H

D

R

D

HO

[1,2]-shiftB

O2

Competing with the NIH ShiftScheme 7.7

deprotonation

The more stabilized the carbocation intermediate, the less favored is a for hydride shift - more deprotonation.

-

B

+ +

R

OD

H

R

H

O D

R

H

HO

H

NIH Shift with Groups Other than HScheme 7.8

p-chloroamphetamine

+

7.20

CH3

NH2

CH3

NH2Cl ClO

CH3

NH2-O

Cl

CH3

NH2O

ClCl

CH3

NH2HO

Toxic Product of Alkene OxygenationScheme 7.14

aflatoxin B1

DNA adduct

7.35

7.347.33

+

OO

O

O O

OCH3H

H H

H OCH3

OO

O

OO

O

O

O

O

O O

OCH3H

HN

NN

HN

dR

O

H2N

OH

Reductive ReactionsTable 7.6

•

RNH2 + R'NH2

R• + X-

Functional group Product

R R'

O

RN NR'

R3N

O

R'

R X

OH

O

R'

R'R

R

R R

R R'

O

R'

O-

R3NO-

RNO2

RNO

RNHOH

RNHOH

RNHOH

RNH2

Reductive DehalogenationScheme 7.43

Cytochrome P450in the absence of O2

May be the cause forHalothane hepatitis

halothane 7.118

7.119

7.120

covalentbinding d c

escapefromenzyme a

e-

b

e- -Br CHCF3

ClC

Cl

CF3

H

H C CF2

Cl F

H

C CF3

ClCH CF2

Cl

H2C

Cl

CF3

R•RH

-F-

-Br-