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

 

Y Rajendraprasad¹, M Bhagavan Raju², KK Rajasekhar^3* 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,

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.

 

 

 

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 region^1,2 .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 metastasis^3,4 .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 degradation^5,6 . 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 subjects^7-11. 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 MMPs^{13 – 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 Version^{18, 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.

 

REFERENCES:

1.       Chambers AF and Matrisian L. Changing views of the role of matrix metalloproteinases in metastasis. J. Natl. Cancer. Inst. 1997: 89: 1260 – 1270. (Cancer lit: 97438141)

2.       Kleiver DE and Stetler-Stevenson WG. Matrix metalloproteinases and metastasis. Cancer chemother pharmacol 1999; 43: Suppl: S42-51. (Cancer lit: 99284450)

3.       Lochter A and Bissell MJ. An odyssey from breast to bone: multistep control of mammary metastases and osteolysis by matrix metalloproteinases. APMIS. 1999. 107 – 128. ([ISI] Medline cancer lit 9204564)

4.       Folkman J. Seminars in medicine of Beth Israel Hospital, Boston. Clinical applications of research on angiogenesis. N. Engl. J. Med. (1995); 333: 1757 – 1763. (Cancer lit 96092309)

5.       Martin DC, Fowlkes JL, Babic B and Khokha R. Insulin-like growth factor II signaling in neoplastic proliferation is blocked by Transgenic expression of the metalloproteinase inhibitor TIMP-1. J. Cell. Boil 1999; 146; 881 – 892. (Cancer lit 99389748)

6.       Manes S, Mira E, Barbacid MM, Cipres A, Buesa JM and Fernandez-Resa P. Identification of insulin-like growth factor-binding protein-1 as a potential physiological substrate for human stromelysin-3. J. B IO Chem 1997; 272: 25706 – 25712. (Cancer lit 97467365)

7.       Nawrocki B, Poletter M, Marchand V, Monteau M, Gillery P and Tournier JM. Expression of matrix metallo proteinases and their inhibitors in human bronchopulmonary carcinomas: Quantificative and morphological analysis. Int. Jour. Cancer. 1997; 72: 556 – 64. (Cancer lit 97402327).

8.       Gonzalez AG, Iturria C, Vadillo F, Teran L, Seloman M, Perez TR, 72-KD(MMP-2) and 92-KD(MMP 9) type IV collagenase production and activity in different histologic types of lung cancer cells. Pathobiology. 1998; 66: 5 -16.(Cancer lit 98237071)

9.       Davidson B, Goldberg I, Liokumovich P, Kopolovic J, Gotlieb WH, Lerner GL. Expression of metalloproteinases and their inhibitors in adenocarcinoma of the uterine cervix. Int.J.Gynecol. pathol. 1998; 17 : 295 – 301. (Cancer lit 99001308)

10.     Bramhall SR. The matrix metalloproteinases and their inhibitors in pancreatic cancer: From molecular science to a chemical application. Int. Jour. Pancreatol 1997; 21: 1 – 12.

11.     Zucker S, Hymowitz M, Conner C, Zarrabi HM, Hurewitz AN, Matrisian L. Measurement of matrix metalloproteinases and tissue inhibitors of metalloproteinases in blood and tissues. Clinical and experimental applications. Ann. NY Acad Sci; 1999, 87: 212 – 27.

12.     Rha SY, Yang WI, Kim JH, Roh JK, Min JS, Lee KS. Different expression patterns of MMP-2 and MMP – 9 in breast cancer. Oncol Rep: 1998; 5: 875 – 879.

13.     Simon C, Juarez J, Nicolson GL, Boyd D. Effect of PD 098059, a specific inhibitor of mitogen-activated protein-kinase, on urokinase expression and in vitro invasion. Cancer Res; 1996; 56: 5369 – 5374.

14.     Bian J, Wang Y, Smith MR, Kim H, Jacobs C, Jackman J. Suppression of invitro tumor growth and induction of suspension cell death by tissue inhibitor of metalloproteinase-3. Carcinogenesis; 1996: 17: 1805 – 1811.

15.     Hasegawa S, Koshikawa N, Momiyama N, Moriyama K, Ichikawa Y, Ichikawa I. Matrylysin-specific antisense oligonucleotide inhibits liver metastasis of human colon cancer cells in a node mouse model. Int. J. Cancer; 1998: 76: 812 – 817.

16.     Brown PD. Matrix metalloproteinase inhibitors. Breast Cancer Res Treat: 1998: 52: 125 – 136.

17.     Lester AM. Drug design and discovery, an overview. In Krogsgaard Larsen P, Liljefors T, Madsen V, Editors. Textbook of Drug design and Discovery. 3^rd ed, London and New York, Taylor and Fracis, 2002; 1 – 53.

18.     ACD labs/chemsketch ver 12.0, Advanced chemistry Development, Toronto, Canada, 2009.

19.     Pharma  Algorithms, Toronto, Canada 2008.

 

 

Received on 05.02.2010        Modified on 09.03.2010

Accepted on 07.04.2010        © AJRC All right reserved

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