IN VITRO AND IN VIVO TO XICITY STUDY OF α-AMINO-ARYLPROPANOIC ACID DERIVATIVES

The anti-inflammatory and antinociceptive activity of S(+)-2-amino-2-(benzylamino) propanoic acid (NPAA 34), R(-)-2-amino-2-(benzylamino) propanoic acid (NPAA 35), S(-)-2-amino-2-methyl-3-phenyl propanoic acid (NPAA 36), S(-)-2-amino-3-(4'-fluoro) phenylpropanoic acid (NPAA 38) and their non-selective COX inhibiting properties demonstrated in our previous studies approved that synthesized alpha-amino-aryl propanoic acid derivatives could serve as a potential source for discover and development of new non-steroidal anti-inflammatory drugs. In view of this the main purpose of presented study was investigation of testified compounds toxicity as an important drugs development step - safety testing. In vitro cytotoxicity by flow cytometry and in vivo toxicity study for determination on certain toxicometry parameters and hazard class assessment were carried out. Obtained results indicated that investigated compound NPAA 38 can be classified to the Category 3 (LD50 > 300 mg/kg) and NPAA 34 to the Category 4 (LD50 > 2000 mg/kg) by Globally harmonized system of classification and labeling of chemicals and third class of the moderately toxic chemicals according WHO classification (LD50 value of NPAA 38 for rat administrated per os was 1300 +/- 102 mg/kg and for NPAA 34 was more than 2000 mg/kg). In a single application of the compounds to the intact rats' skin irritating effect was not revealed while they have a moderate irritant effect on the mucous membranes of rabbit's eyes. According to flow cytometry data, the S(+)-2-amino-2-(benzylamino) propanoic acid (NPAA 34) and S(-)-2-amino-2-methyl-3-phenyl propanoic acid (NPAA 36) do not display cytotoxicity. It was demonstrated, that in 500 mu M concentrations the total number of peripheral blood mononuclear cells (PBMC) and monocytes was not changed significantly in presence of investigated non protein amino acids.