Insilico Prodrug Designing of Some Matrix Metallo Proteinase Inhibitors Derived From Tanomastat

 

Y Rajendraprasad1, M Bhagavan Raju2, KK Rajasekhar3* and S Sowjanya3

1Department of Pharmaceutical Sciences, Andhra University, Visakhapatnam- 530003, AP, India.

2CMR College of Pharmacy, Hyderabad, AP, India.

3Dept. of Pharmaceutical Chemistry, Sri Padmavathi School of Pharmacy, Tiruchanoor, Tirupati -517503, AP,

*Corresponding Author E-mail: komarlakrs@gmail.com

 

ABSTRACT:

The present work describes the insilico prodrug designing of Tanomastat, a matrix metalloproteinase inhibitor. Tanomastat was selected as a lead and a series of prodrug-like molecules derived from it were generated. The pharmacokinetic and toxicity profile of these prodrug-like molecules was obtained by using ADME and TOX boxes web version of pharma Algorithms and ACD labs Chem Sketch software version 12.0. All prodrug-like molecules were predicted to be lipophilic, less toxic with an enhaced protein binding and better therapeutic efficacy.In conclusion, ADME and Toxicity properties of these molecules suggest advantages over Tanomastat.

 

KEYWORDS: Insilico prodrug designing, Tanomastat, Matrix Metallo Proteinase Inhibitor (MMPI), Pharmacokinetic and Toxicity profile.

 


 

INTRODUCTION:

Matrix Metallo Proteinases (MMPs) are a family of Zinc-dependent neutral endopeptidases that are collectively capable of degrading essentially all of the components of the extracellular matrix. The three common structural domains, shared by all MMPS, are the propeptide domain, the catalytic domain and the haemopexin-like C-terminal domain which is linked to the catalytic domain by a flexible hinge region1,2 .Tumor growth, invasion and metastasis are a multistep and complex process that includes cell division and proliferation, proteolytic digestion of the extracellular matrix, cell migration through basement membranes to reach the circulatory system, and remigration and growth of tumors at the metastatic sites. MMPs degrade the basement membrane and extracellular matrix, thus facilitating the invasion of malignant cells through connective tissues and blood vessel walls and resulting in the establishment of metastasis3,4 .The degradation of the extracellular matrix by MMPs not only facilitates metastasis but also promotes tumor growth by increasing the bioavailability of growth factors that reside in the extracellular matrix and are released during degradation5,6 . Numerous studies in a variety of tumor types, including lung, colon, breast and pancreatic carcinomas, demonstrate over expression of MMPs in malignant tissues in comparison to adjacent normal tissues.

 

n addition, the plasma and urine levels of MMPs are elevated in patients with cancer compared with the healthy subjects7-11. Further, analysis of cellular components derived from primary tumor tissues of their corresponding lymph node metastasis demonstrated increased expression of MMPs in the metastatic tissue, indicating that MMP expression is a component of metastatic process12.

 

As MMPs play a pivotal role in the process of malignant progression, the pharmacological inhibition of MMP activity can markedly inhibit the invasiveness of primary and metastatic tumors and therefore, be of therapeutic benefit to patients with cancer. Various strategies has been studied to inhibit MMP activity. Few of them are inhibition of signal transduction or use of specific antisense oligonucleotides to inhibit expression of MMPs and use of natural compounds to inhibit MMPs13 – 15 . However, lack of effective methods of systemic gene delivery and etc has limited the clinical utility of these strategies, whereas the development of synthetic inhibitors of MMPs has been actively pursued and widely tested in clinical trials16. Tanomastat (BA712 – 9566) is an synthetic nonpeptidomimetic inhibitor of MMP-2 and MMP-3. It was developed by Bayer Corporation (Pittsburgh, PA, USA) and was found to be effective in in vivo and in vitro studies. But, its development as an anticancer agent was halted in clinical trials.

 

The chemical structure of Tanomastat reveals that it has a free carboxylic acid group as pharmacophore and a free aromatic para position. It is a well known fact that xenobiotics containing free carboxylic acid group, directly enters into phase-II metabolic conjugation and gets rapidly eliminated from the body. Moreover, xenobiotics with free aromatic para position will undergo phase-I metabolic oxidation involving a toxic intermediate called “arene oxide”. This toxic intermediate slowly becomes more polar arenol and enters into phase-II conjugation and gets excreted. These two are the probable reasons for failure of Tanomastat in clinical trials. Because of rapid elimination and toxicity, it’s development was halted. The possible way to enhance its drug-likeness is by bioreversible chemical derivatization.

 

Therefore, we made an attempt to enhance drug-likeliness of Tanomastat through insilico prodrug designing.

 

MATERIALS AND METHODS:

LEAD MOLECULE:

A review of literature reveals that Tanomastat is an effective inhibitor of MMPs with poor pharmacokinetic profile. In an effort to enhance the pharmacokinetics and reduce the toxicity of Tanomastat, we selected it as a lead molecule to generate prodrug-like molecules with anticipated anticancer activity.

 

GENERATION OF PRODRUG-LIKE MMPIs:

The importance of optimizing molecules during early drug development not only for efficacy, pharmacokinetic and biopharmaceutical properties but also for their toxicological properties is now widely recognized. Moreover, it is usual to start with molecules that appear to be drug-like at the outset rather than to make a hit drug-like later17. Therefore, 65 MMPIs were generated from Tanomastat by converting carboxylic acid group into ester and amide functionalities, and by introducing halogen atoms at para position of phenyl ring. Structures of prodrug-like molecules were drawn through chemsketch software. Each 2D chemical structure was systematically built, that is, the basic nucleus was kept unaltered and the above mentioned substituents were added accordingly. All these structures were saved and exported to ADME and Tox boxes web version.

 

IN SILICO ADME AND TOX PROFILE:

Unfavorable ADME and toxicity properties have been identified as a major cause of failure for candidate molecules in drug development. So many potent compounds were failed to progress into clinical studies due to problems achieving a desirable pharmacokinetic profile. Consequently, there is increasing interest in the early prediction of these properties, with the objective of increasing the success rate of compounds reaching development and market. The pharmacokinetic, biopharmaceutical and toxicity properties were calculated through ACD labs Chem Sketch programme and ADME and Tox boxes of pharma Algorithm Web Version18, 19.

 

RESULTS AND DISCUSSION:

In the present study, Tanomastat was selected as lead molecule and 65 prodrug-like molecules with anticipated MMP inhibitory and anticancer activity were generated. Selected biopharmaceutical, pharmacokinetic and toxicity properties were calculated using softwares. Structural details and ADME and Tox profile was shown in Table no: 1 and Table no: 2 respectively.

 

Table No: 1 shows that molar refractivity, log D, parachor, refractive index and polarisability are enhanced as molecular weight increases. This can be attributed to the conversion of free carboxylic acid group into ester and amide functionality. Introduction of alkyl groups on amide nitrogen has more positive impact on these properties than other structural modifications. Hydrogen bond donating ability was completely absent in ester derivatives when compared to amide derivatives. Among amide derivatives, substitution on amide nitrogen reduces hydrogen bond donating ability. An increase in molecular weight enhances the lipophilicity and reduces aqueous solubility. This again can be attributed to steric bulkiness afforded by alkyl groups in ester and amide derivatives. Introduction of halogens also increases lipophilicity and reduces aqueous solubility. The order of impact on lipophilicity and aqueous solubility among halogens seems to be I>Br>Cl>F. This is propably due to high electronegativity of fluorine (induced dipole and polarity) and size of iodine.

 

Table No: 2 shows that all the amide and ester derivatives exhibit marked molecular flexibility(number of rotatable bonds). All these molecules were predicted to be absorbed via passive diffusion and metabolised  by first pass with almost same rate of absorption. Both oral bioavailability and toxicity (LD50 in mice) are enhanced in amide derivatives whereas protein binding and volume of distribution are enhanced in ester derivatives.

 

Prodrug-like molecules derived from Tanomastat shows greater lipophilicity, molar refractivity and parachor. Molar refractivity is an additive property of the molecule. A larger MR value for a substituent corresponds to a larger steric bulk and greater tendency to interact via dispersive forces. Presence of more number of hydrogen bond donors and acceptors aids in increasing aqueous solubility. Presence of rotatable bonds in a molecule indicates molecular flexibility, which is essential to attain 3D complementary structure and effective target binding.

 

The prodrug approach may be useful in reducing or circumventing first-pass metabolism where the obvious approach is to mask the metabolic labile functionalities in the drug molecule. This, however, requires regeneration of the drug after the prodrug has entered systemic circulation. Prodrug design has been used to improve the performance of drugs by overcoming various barriers to drug delivery, transportation and etc. In most cases, this has been accomplished by formation of prodrug derivatives altering the basic physicochemical characteristic of a drug substance which in addition to chemical stability encompasses lipophilicity and aqueous stability.

 

 


TABEL 1:  STRUCTURAL DETAILS AND SELECTED PHYSICOCHEMICAL PROPERTIES  OF 65 PRODRUG LIKE MOLECULES  DERIVED FROM TANOMASTAT

S. No

Code

R

X

Molecular weight

Log D

`Molar refractivity

(cm3)

Parachor (cm3)

Refractive index

Polarisability×10-24

(cm3)

No of H-bond

Aqueous solubility

(mg/ml)

Donors

Acceptors

1

TEPB1

-O.CH3

-F

442.931

5.88

118.85±0.4

915.4±6.0

1.623±0.03

47.11±0.5

0

3

0.00033

2

TEPB2

-O.CH3

-Cl

459.385

6.37

123.57±0.4

945.2±6.0

1.639±0.03

48.98±0.5

0

3

0.00013

3

TEPB3

-O.CH3

-Br

503.837

7.04

126.46±0.4

959.2±6.0

1.653±0.03

50.13±0.5

0

3

0.00013

4

TEPB4

-O.CH3

-I

550.837

7.31

131.66±0.4

982.0±6.0

1.671±0.03

52.19±0.5

0

3

0.00012

5

TEPB5

-O.C2H5

-F

456.957

6.37

123.48±0.4

955.5±6.0

1.616±0.03

48.95±0.5

0

3

0.00021

6

TEPB6

-O.C2H5

-Cl

473.412

5.88

128.20±0.4

985.3±6.0

1.631±0.03

50.82±0.5

0

3

0.00035

7

TEPB7

-O.C2H5

-Br

517.863

7.52

121.09±0.4

999.2±6.0

1.645±0.03

51.97±0.5

0

3

0.00008

8

TEPB8

-O.C2H5

-I

564.864

7.79

136.29±0.4

1022.1±6.0

1.662±0.03

54.03±0.5

0

3

0.00036

9

TEPB9

-O.CH2.CH2.CH3

-F

470.984

6.86

128.11±0.4

995.6±6.0

1.610±0.03

50.79±0.5

0

3

0.00015

10

TEPB10

-O.CH2.CH2.CH3

-Cl

487.431

8.25

132.83±0.4

1025.3±6.0

1.625±0.03

52.65±0.5

0

3

0.00005

11

TEPB11

-O.CH2.CH2.CH3

-Br

531.890

8.01

135.72±0.4

1039.3±6.0

1.638±0.03

53.80±0.5

0

3

0.00006

12

TEPB12

-O.CH2.CH2.CH3

-I

578.890

8.28

140.92±0.4

1062.1±6.0

1.654±0.03

55.86±0.5

0

3

0.00006

13

TEPB13

-O.CH.(CH3)2

-F

470.984

6.62

128.09±0.4

993.5±6.0

1.609±0.03

50.78±0.5

0

3

0.00013

14

TEPB14

-O.CH.(CH3)2

-Cl

487.438

7.75

132.81±0.4

1023.3±6.0

1.623±0.03

52.65±0.5

0

3

0.00007

15

TEPB15

-O.CH.(CH3)2

-Br

531.890

7.77

135.70±0.4

1037.2±6.0

1.636±0.03

53.79±0.5

0

3

0.00005

16

TEPB16

-O.CH.(CH3)2

-I

578.890

8.05

140.90±0.4

1060.1±6.0

1.653±0.03

55.85±0.5

0

3

0.00026

17

TEWPB1

-O.CH3

-H

424.940

6.33

118.74±0.4

908.1±6.0

1.632±0.03

47.07±0.5

0

3

0.00043

18

TEWPB2

-O.C2H5

-H

438.967

6.82

123.37±0.4

948.1±6.0

1.625±0.03

48.90±0.5

0

3

0.00027

19

TEWPB3

-O.CH2.CH2.CH3

-H

452.994

7.30

128.00±0.4

988.2±6.0

1.619±0.03

50.74±0.5

0

3

0.00019

20

TEWPB4

-O.CH.(CH3)2

-H

452.994

7.07

127.98±0.4

986.2±6.0

1.617±0.03

50.73±0.5

0

3

0.00017

21

TAPB1

-NH2

-F

427.920

4.67

116.10±0.4

884.7±6.0

1.649±0.03

46.02±0.5

2

3

0.00037

22

TAPB2

-NH2

-Cl

444.374

5.82

120.82±0.4

914.5±6.0

1.663±0.03

47.89±0.5

2

3

0.00029

23

TAPB3

-NH2

-Br

488.825

5.82

123.71±0.4

928.4±6.0

1.682±0.03

49.04±0.5

2

3

0.00015

24

TAPB4

-NH2

-I

535.826

6.09

128.71±0.4

951.3±6.0

1.701±0.03

51.10±0.5

2

3

0.00057

25

TAPB5

-NH.CH3

-F

441.946

4.92

120.76±0.4

923.3±6.0

1.632±0.03

47.87±0.5

1

3

0.00079

26

TAPB6

-NH.CH3

-Cl

458.401

6.07

125.48±0.4

953.1±6.0

1.648±0.03

49.74±0.5

1

3

0.00063

27

TAPB7

-NH.CH3

-Br

502.852

6.07

128.37±0.4

967±6.0

1.662±0.03

50.89±0.5

1

3

0.00032

28

TAPB8

-NH.CH3

-I

549.852

6.34

133.57±0.4

989.9±6.0

1.680±0.03

52.95±0.5

1

3

0.00032

29

TAPB9

-NH.C2H5

-F

455.973

5.40

125.39±0.4

963.4±6.0

1.625±0.03

49.71±0.5

1

3

0.00058

30

TAPB10

-NH.C2H5

-Cl

472.427

6.55

130.11±0.4

993.2±6.0

1.640±0.03

51.58±0.5

1

3

0.00044

31

TAPB11

-NH.C2H5

-Br

516.878

6.55

133.00±0.4

1007.1±6.0

1.654±0.03

52.72±0.5

1

3

0.00023

32

TAPB12

-NH.C2H5

-I

563.879

6.82

138.20±0.4

1030.0±6.0

1.671±0.03

54.79±0.5

1

3

0.00069

33

TAPB13

-NH.CH2.CH2.CH3

-F

469.999

5.89

130.02±0.4

1003.5±6.0

1.618±0.03

51.54±0.5

1

3

0.00041

34

TAPB14

-NH.CH2.CH2.CH3

-Cl

486.454

7.04

134.74±0.4

1033.3±6.0

1.633±0.03

53.41±0.5

1

3

0.00031

35

TAPB15

-NH.CH2.CH2.CH3

-Br

530.905

7.04

137.63±0.4

1047.2±6.0

1.646±0.03

54.56±0.5

1

3

0.00016

36

TAPB16

-NH.CH2.CH2.CH3

-I

577.905

7.31

142.83±0.4

1070.1±6.0

1.663±0.03

56.62±0.5

1

3

0.00057

37

TAPB17

-NH.CH.(CH3)2

-F

469.999

5.66

130.00±0.4

1001.4±6.0

1.617±0.03

51.53±0.5

1

3

0.00041

38

TAPB18

-NH.CH.(CH3)2

-Cl

486.454

6.81

134.72±0.4

1031.2±6.0

1.632±0.03

53.40±0.5

1

3

0.0003

39

TAPB19

-NH.CH.(CH3)2

-Br

530.905

6.81

137.61±0.4

1045.1±6.0

1.645±0.03

54.55±0.5

1

3

0.00016

40

TAPB20

-NH.CH.(CH3)2

-I

577.905

7.08

142.81±0.4

1068.0±6.0

1.661±0.03

56.61±0.5

1

3

0.0005

41

TAPB21

-N.(CH3)2

-F

455.973

5.59

125.62±0.4

961.5±6.0

1.629±0.03

49.80±0.5

0

3

0.00073

42

TAPB22

-N.(CH3)2

-Cl

472.427

6.74

130.43±0.4

991.2±6.0

1.644±0.03

51.67±0.5

0

3

0.00056

43

TAPB23

-N.(CH3)2

-Br

516.878

6.74

133.23±0.4

1005.2±6.0

1.658±0.03

52.81±0.5

0

3

0.0003

44

TAPB24

-N.(CH3)2

-I

563.879

7.0

138.43±0.4

1028.1±6.0

1.675±0.03

54.88±0.5

0

3

0.00073

45

TAPB25

-N.(C2H5)2

-F

484.026

6.56

134.88±0.4

1041.6±6.0

1.616±0.03

53.47±0.5

0

3

0.00032

46

TAPB26

-N.(C2H5)2

-Cl

500.480

7.71

139.60±0.4

1071.4±6.0

1.630±0.03

55.34±0.5

0

3

0.00025

47

TAPB27

-N.(C2H5)2

-Br

544.932

7.71

142.49±0.4

1085.3±6.0

1.643±0.03

56.49±0.5

0

3

0.00012

48

TAPB28

-N.(C2H5)2

-I

591.932

7.98

147.69±0.4

1108.2±6.0

1.659±0.03

58.55±0.5

0

3

0.00035

49

TAPB29

-N.(CH2.CH2.CH3)2

-F

512.079

7.53

144.15±0.4

1121.8±6.0

1.606±0.03

57.14±0.5

0

3

0.00017

50

TAPB30

-N.(CH2.CH2.CH3)2

-Cl

528.533

8.68

148.86±0.4

1151.5±6.0

1.619±0.03

59.01±0.5

0

3

0.00013

51

TAPB31

-N.(CH2.CH2.CH3)2

-Br

572.985

8.68

151.76±0.4

1165.5±6.0

1.630±0.03

60.16±0.5

0

3

0.00007

52

TAPB32

-N.(CH2.CH2.CH3)2

-I

619.985

8.95

156.95±0.4

1188.4±6.0

1.645±0.03

62.22±0.5

0

3

0.00026

53

TAPB33

-N.(CH2.CH2.CH3)2

-F

512.079

7.07

144.10±0.4

1117.7±6.0

1.603±0.03

57.12±0.5

0

3

0.00012

54

TAPB34

-N.(CH2.CH2.CH3)2

-Cl

528.533

8.22

148.81±0.4

1147.4±6.0

1.616±0.03

58.99±0.5

0

3

0.00009

55

TAPB35

-N.(CH2.CH2.CH3)2

-Br

572.985

8.22

151.71±0.4

1161.4±6.0

1.628±0.03

60.14±0.5

0

3

0.00005

56

TAPB36

-N.(CH2.CH2.CH3)2

-I

619.985

8.49

156.91±0.4

1184.3±6.0

1.643±0.03

62.20±0.5

0

3

0.00015

57

TAWPB1

-NH2

-H

409.929

5.11

115.99±0.4

877.4±6.0

1.660±0.03

45.98±0.5

2

3

0.00049

58

TAWPB2

-NH.CH3

-H

423.956

5.36

120.65±0.4

916.0±6.0

1.642±0.03

47.83±0.5

1

3

0.00107

59

TAWPB3

-NH.C2H5

-H

437.982

5.85

125.28±0.4

956.0±6.0

1.634±0.03

49.66±0.5

1

3

0.00077

60

TAWPB4

-NH.CH2.CH2.CH3

-H

452.009

6.33

129.91±0.4

996.1±6.0

1.627±0.03

51.50±0.5

1

3

0.00054

61

TAWPB5

-NH.CH.(CH3)2

-H

452.009

6.10

129.89±0.4

994.1±6.0

1.626±0.03

51.49±0.5

0

3

0.00054

62

TAWPB6

-N(CH3)2

-H

437.982

6.03

125.51±0.4

954.1±6.0

1.638±0.03

49.75±0.5

0

3

0.00097

63

TAWPB7

-N.(C2H5)2

-H

466.035

7.00

134.77±0.4

1034.3±6.0

1.625±0.03

53.42±0.5

0

3

0.00042

64

TAWPB8

-N(CH2.CH2.CH3)2

-H

494.089

7.97

144.03±0.4

1114.4±6.0

1.613±0.03

57.10±0.5

0

3

0.00022

65

TAWPB9

-N[CH.(CH3)2]2

-H

494.089

7.51

143.99±0.4

1110.3±6.0

1.611±0.03

57.08±0.5

0

3

0.00016


TABLE 2: ADME  AND TOX PROFILE

S. No

Code

Molecular Flexibility                          ( number of rotatable bonds)

Plasma Protein binding(%)

Volume of distribution  (l/kg)

Oral Bioavailability

LD 5o  in  Mice(mg/kg)

Oral

IP

IV

SC

1

TEPB1

9

99.78

3.93

<30%

1200

510

73

460

2

TEPB2

9

99.95

4.60

<30%

1400

490

76

420

3

TEPB3

9

99.95

4.60

<30%

1500

520

82

660

4

TEPB4

9

99.97

4.83

<30%

1600

490

100

610

5

TEPB5

10

99.88

4.09

<30%

1200

500

64

450

6

TEPB6

10

99.97

5.02

<30%

1500

470

68

420

7

TEPB7

10

99.98

5.02

<30%

1500

400

72

680

8

TEPB8

10

99.99

5.27

<30%

1000

400

91

620

9

TEPB9

11

99.94

4.46

<30%

1300

370

61

450

10

TEPB10

11

99.98

5.47

<30%

1500

460

63

420

11

TEPB11

11

99.99

5.47

<30%

1600

490

69

700

12

TEPB12

11

99.99

5.74

<30%

1100

340

86

640

13

TEPB13

10

99.92

4.28

<30%

1200

440

52

360

14

TEPB14

10

99.98

5.25

<30%

1300

330

54

330

15

TEPB15

10

99.98

5.25

<30%

1400

360

58

590

16

TEPB16

10

99.99

5.51

<30%

1500

420

72

540

17

TEWPB1

9

99.86

4.26

<30%

960

490

75

390

18

TEWPB2

10

99.93

4.64

<30%

1400

470

67

390

19

TEWPB3

11

99.96

4.82

<30%

1000

410

63

390

20

TEWPB4

10

99.95

4.63

<30%

1300

420

54

310

21

TAPB1

8

99.03

2.64

30-70%

840

350

79

340

22

TAPB2

8

99.76

3.89

30-70%

980

260

40

420

23

TAPB3

8

99.80

3.70

30-70%

1000

360

42

460

24

TAPB4

8

99.88

3.89

30-70%

1100

340

62

420

25

TAPB5

8

99.31

2.76

30-70%

640

300

65

300

26

TAPB6

8

99.83

3.87

30-70%

750

240

68

250

27

TAPB7

8

99.86

3.40

30-70%

790

300

73

410

28

TAPB8

8

99.91

4.06

30-70%

850

280

92

370

29

TAPB9

9

99.63

2.75

30-70%

720

300

58

290

30

TAPB10

9

99.91

4.04

30-70%

840

280

60

270

31

TAPB11

9

99.92

4.04

30-70%

840

300

64

440

32

TAPB12

9

99.95

4.24

30-70%

850

240

82

400

33

TAPB13

10

99.80

3.59

30-70%

760

290

55

290

34

TAPB14

10

99.95

4.40

30-70%

860

270

57

270

35

TAPB15

10

99.96

4.41

30-70%

900

290

61

430

36

TAPB16

10

99.98

4.62

30-70%

880

270

77

400

37

TAPB17

9

99.74

3.44

30-70%

710

270

47

250

38

TAPB18

9

99.94

4.23

30-70%

660

260

48

340

39

TAPB19

9

99.95

4.23

30-70%

870

270

52

360

40

TAPB20

9

99.97

4.44

30-70%

730

260

65

330

41

TAPB21

8

99.70

3.55

30-70%

600

220

49

260

42

TAPB22

8

99.93

4.36

30-70%

700

210

51

220

43

TAPB23

8

99.94

4.36

30-70%

730

210

54

350

44

TAPB24

8

99.96

4.58

30-70%

790

210

69

320

45

TAPB25

10

99.91

4.34

30-70%

660

210

38

280

46

TAPB26

10

99.98

5.33

30-70%

530

200

40

240

47

TAPB27

10

99.98

5.33

30-70%

800

210

43

370

48

TAPB28

10

99.99

5.59

30-70%

550

200

53

340

49

TAPB29

12

99.98

5.38

30-70%

690

200

34

300

50

TAPB30

12

99.99

6.61

30-70%

800

190

36

230

51

TAPB31

12

100.00

6.61

30-70%

830

200

38

400

52

TAPB32

12

100.00

6.94

30-70%

880

190

47

360

53

TAPB33

10

99.96

4.75

30-70%

570

170

25

210

54

TAPB34

10

99.99

5.83

30-70%

660

160

26

160

55

TAPB35

10

99.99

5.83

30-70%

690

170

27

270

56

TAPB36

10

99.99

6.13

30-70%

730

130

34

250

57

TAWPB1

8

99.38

2.86

30-70%

780

330

83

420

58

TAWPB2

8

99.56

2.99

30-70%

740

280

67

370

59

TAWPB3

9

99.77

3.74

30-70%

820

280

60

250

60

TAWPB4

10

99.87

4.08

30-70%

850

270

57

250

61

TAWPB5

9

99.84

3.91

30-70%

670

260

48

210

62

TAWPB6

8

99.81

4.04

30-70%

500

210

51

210

63

TAWPB7

10

99.95

4.70

30-70%

760

200

40

230

64

TAWPB8

12

99.98

5.83

30-70%

800

190

36

220

65

TAWPB9

10

99.97

5.14

30-70%

660

160

26

160

 

TEPB – Tanomastat Ester with Para Blocker, TEWPB – Tanomastat Ester Without Para Blocker, TAPB – Tanomostat Amide with Para Blocker.

TAWPB – Tanomostat Amide Without Para Blocker, IP – Intraperitoneal , IV- Intravenous , SC – Subcutaneous.


The function of a drug which reaches the receptor site for therapeutic response is largely governed by dissolution and transport process. These processes are primarily dependent on the lattter two fundamental physicochemical properties.

 

The phrase “drug-like” generally means molecules which contain functional groups and/or have properties consistent with the majority of known drugs. Evaluation of drug-likeness involves prediction of ADME and Toxicity properties. Insilico prediction of drug-likeness at an early stage involves evaluation of various ADME and Toxicity properties using computational methods.

 

CONCLUSION:

Determination of various pharmacokinetic and toxicity properties of xenobiotics is an important step in drug discovery and formulation process.This is normally done using animal models. Keeping in mind the vast extent of economy that has to be invested in this process we came up with a new idea of using softwares to determine these parameters. The present study successfully explored the possibility of using computers and softwares in this part of drug discovery.

 

From the present study , it can be concluded that all the prodrug-like molecules shows advantages over Tanomastat and probably this work will help in repositioning Tanomastat as a MMPI ,atleast in a prodrug form.

 

Studies have indicated that poor pharmacokinetics and toxicity are the most important causes of high attrition rates in drug development and it has been widely accepted that these areas should be considered as early as possible in the drug discovery process, thus improving the efficiency and cost-effectiveness of the pharmaceutical industry. Resolving the pharmacokinetic and toxicological properties of drug candidates remains a key challenge for drug developers.

 

ACKNOWLEDGEMENT:

The authors are thankful to Smt P. Sulochana, M.A., B.Ed, L.L.B., Chairperson, Sri Padmavathi Group of Educational Institutions, Tiruchanoor, Tirupati for providing us facilities to carry out this research work.

 

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Received on 05.02.2010        Modified on 09.03.2010

Accepted on 07.04.2010        © AJRC All right reserved

Asian J. Research Chem. 3(2): April- June 2010; Page 411-415

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