Quantitative structure-activity relations of chymotrypsin. The predictive value of correlation equations

Journal of Medicinal Chemistry
1977.0

Abstract

It is shown that inhibition constants against chymotrypsin for new congeners of the type R₁C(=O)R₂ are well predicted by a correlation equation published earlier. Now that the field of quantitative structure-activity relationships (QSAR) has reached a modest level of maturity, it becomes of increasing interest to begin to more rigorously assess the predictive value of correlation equations. Toward this end we have recently surveyed the literature and summarized examples where previously formulated equations were later found to give good correlations with new data. Rouot et al. have recently illustrated the forecasting ability of QSAR with clonidine analogues. In addition, we have now shown that a QSAR for 102 antimalarials gives good results for over 100 new analogues. In this report we wish to show that a QSAR formulated for the inhibition of chymotrypsin by inhibitors of the type R₁C(=O)R₂ applies to new data. A series of classical quinazoline analogues of folic and isofolic acids was evaluated for inhibitory activity against the dihydrofolate reductases from rat liver and from Streptococcus faecium. Included in this group were the known active antitumor agents methasquin and chlorasquin as well as methotrexate. Two new compounds, N¹⁰-formyl-5,8-deazaaminopterin and N¹⁰-formyl-5,8-deazafolic acid, were synthesized specifically for this study. The latter displayed modest activity against L1210 leukemia in mice.

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