METABOLISM DRUG DISCOVERY

7/30/2019 METABOLISM DRUG DISCOVERY

1/17

Cilastatin metabolism led drug discovery

Medicinal Chemistry


2/17


3/17

Beta Lactams Cell Wall synthesis inhibitorsBeta Lactams Cell Wall synthesis inhibitors

Meropenem Faropenem Sanfitrinem

Panipenem Doripenem ErtapenemImipenem


4/17


5/17

ImipenemImipenem

During the development of During the development of carbapenems, imipenem (N-carbapenems, imipenem (N-formidoyl derivative of formidoyl derivative of thienamycin) had the highestthienamycin) had the highestpotency, broad spectrumpotency, broad spectrumactivity and lack of crossactivity and lack of crossresistance.resistance.

Disadvantages: Low level of Disadvantages: Low level of

urinary concentrations of theurinary concentrations of theantibiotic due to extensiveantibiotic due to extensiverenal metabolism;renal metabolism;nephrotoxicitynephrotoxicity

N

O

HHHO

O

OHH3C

S

NH2

Thienamycin

antibiotic

N

O

HHHO

O

OHH3 C

S

NH

NH

Imipenemantibiotic


6/17

Human Renal dehydropeptidaseHuman Renal dehydropeptidase

Membrane bound glycoprotein involved in hydrolysis of dipeptides locatedMembrane bound glycoprotein involved in hydrolysis of dipeptides locatedin renal cortexin renal cortex

Metallo enzyme (Zinc cofactor)Metallo enzyme (Zinc cofactor)

Metabolism of glutathione its conjugates and some drugs eg. Imipenem,Metabolism of glutathione its conjugates and some drugs eg. Imipenem,PanipenemPanipenem

To date the only mammalian enzyme able to hydrolyze the beta-lactam ringTo date the only mammalian enzyme able to hydrolyze the beta-lactam ring

Dehydropeptidase-I is responsible for hydrolyzing the beta lactam ring of Dehydropeptidase-I is responsible for hydrolyzing the beta lactam ring of imipenem, inactivating it but does not affect penicillins or cephalosporinsimipenem, inactivating it but does not affect penicillins or cephalosporins


7/17

CilastatinCilastatin

Cilastatin was developed as a reversible, competitive inhibitor of dehydropeptidase I (DHP-I) onCilastatin was developed as a reversible, competitive inhibitor of dehydropeptidase I (DHP-I) onthe basis of the structural similarities between the scissile bonds in imipenem and dehydropeptidesthe basis of the structural similarities between the scissile bonds in imipenem and dehydropeptides

In the presence of cilastatin, dehydropeptidase does not open the lactam ring of imipenemIn the presence of cilastatin, dehydropeptidase does not open the lactam ring of imipenem(Clinically it is given as 1 : 1 combination)(Clinically it is given as 1 : 1 combination)

Affinity for cilastatin is 30000 times greater than imipenem for DHP-I enzyme Affinity for cilastatin is 30000 times greater than imipenem for DHP-I enzyme

Cilastatin prevents renal re-absorption of imipenem and increases its excretion in urine, therebyCilastatin prevents renal re-absorption of imipenem and increases its excretion in urine, therebyimipenems usage is now broadened to indications such as urinary tract infection which wasimipenems usage is now broadened to indications such as urinary tract infection which wasotherwise limited to only systemic infections.otherwise limited to only systemic infections.

Because in the absence of cilastatin, required concentration of of active drug of imipenem in urineBecause in the absence of cilastatin, required concentration of of active drug of imipenem in urine

was not feasible since dehydropeptidase metabolises imipenem in kidney.was not feasible since dehydropeptidase metabolises imipenem in kidney.

HN

S

COOHH 2N

OHO

O


8/17

(Z)-2-benzamidobut-2-enoic acidLead

H

HN

COOH

O

H

HN

COOH

O

NH2

glycyl dehydrophenylalanine

A Substrate for Dehydropeptidase

H

HN

COOH

RR 1


9/17

(Z )-2-(Acylamino)-2-butenoic acids Activity ContdH

HN

COOH

R

O

MeO

Cl

O

S

70

(2.5)

(0)

(7)

(3)

(21)

(30)

(3)

10

K i M

(% inhibitionat 100 M)

K i M


K i M


2-benzamido-2-butenoic acid as a lead, a number of other aryl and heteroaryl groups were testedas replacements for phenyl with unimpressive results.


10/17

H

HN

COOH

R

O

R= Me

Et

(CH 2)2CH 3

(CH 2)3CH 3

(CH 2)4CH 3

(CH 2)5 CH 3

(CH 2)9CH 3

(CH 2)10 CH 3

CH 2CH(CH 3)2

(CH 2)2CH(CH 3)2

(CH 2)4CH(CH 3)2

CH=C(CH 3)2

(12)

(43)

10

30

32

(54)

(49)

19

35

6

14

(57)

28

CH(Me)CH(CH 3)23.3

CH( i Pr) 2 (13)

(Z )-2-(Acylamino)-2-butenoic acids - Activity

K i M


K i M


K i M



11/17

(Z )-2-(Acylamino)-2-butenoic acids ActivityContd H

HN

COOH

R

O

3

30

15

(3)

22

9.8

25

(33)

K i M(% inhibitionat 100 M)

K i M


Other than the cyclopropyl shown above larger cycloalkyl groups exerted less activity


12/17

(Z )-2-(Acylamino)-2-butenoic acids Activity ContdH

HN

COOH

R

O

Cl

Cl

Br

Br

(16)

1.7

12

1.6

6.5

0.4

0.19

19.8

1.6

4.6

7.2

(10)

0.08

0.03

(11)

K i M


K i M




( )

(+)

(-)


13/17

JMC 1987 30 1074

H

HN

COOH

O

R

R= H

Et

(CH 2)2CH 3

(CH 2 )3 CH 3

(CH 2)4CH 3

(CH 2)7CH 3

(CH 2)2CH=CH 2

CH 2 CF 3

52

0.18

10

0.11

0.11

8.8

0.11

0.14

0.240.092

N33.45

(CH 2)4CN 0.21

4N

N

0.84

N4

1.10

N4 0.91OH

N41.09

(CH 2)5NH2 1

(CH 2 )5 OH 0.23

(CH 2)3COOH0.048

S POH

3

OOH

0.22

OOH


14/17

H

HN

COOH

O

R=

(CH 2)2COOH0.14

0.27

0.28

S

NH 2

OH

O

2

SOMe

2

O

SONa

3

OO

0.087

NOH

3

O

0.56

S

NH 2

OH

O

30.21

S

NH 2

OH

O

3

0.19

Cilastatin 0.11

NH

POH

4

OOH

0.4

NH

POH

4

OOH

0.28

S3

N

COOH

0.04

S3

N

OH

0.13

S CONH 240.25

NOH

5

O

0.4

Na +O

O -

HN O

SO

OH

NH2

JMC 1987 30 1074

Compared with the basic amines, acidic groups such phosphates and carboxylates showed better activity


15/17

Na +O

O -

HN O

Na +O

O -

HN O

SO

OH

NH2

Compd 1 Cilastatin

SAR study reveals that a large number of diverse substituents can be toleratedin R1 of the 2-(2,2-dimethylcyclopropylamino)-2-butenoic acid derivatives

,- unsaturated acid moiety and the allylic CH2 of the R1 chain are importantfor the activity

Compd 1 and cilastatin showed desired pharmacokinetic properties, whereinCompd 1 caused local irritation when injected repeatedly at high doses inanimals

N-acetyl cilastatin is the active metabolite found in body which is also twice asactive as cilastatin. But half life of N-acetyl cilastatin is lesser than cilastatin andhence it could not be profiled for further studies

H

HN

COOH

R1

O

Highlights - SAR


16/17

EP0048301 & WO 03018544

Z)-7-[(2R)-2-amino-3-hydroxy-3-oxopropyl]sulfanyl-2-{[(1S)-2,2-dimethylcyclopropanecarbonyl]amino}hept-2-enoic acid

S S

COOEt

Br(CH 2)5Br S SBr COOEt5

COOEt

HBr / HOAc NaHDMFToluene

O

Br 5 COOH

O

Br 5

NBS, ACN

NH2

O

H COOH

Br 4 HN CO

H COOH

S 4 HN CO

NH2

HS

O

OHH2N

ToluenePTSA (cat.)reflux

NaOH

OH

O


17/17

METABOLISM DRUG DISCOVERY

Documents

Transcript of METABOLISM DRUG DISCOVERY