title: Synthesis and Caco-2 cell permeability of N-substituted anthranilamide esters as ADP inhibitor in platelets.
abstract: Twelve N-substituted anthranilamide esters (1-5, 8, 9, 12, 13, and 15-17) were synthesized and evaluated for their ability to inhibit the in vitro aggregation by washed human platelets induced by adenosine 5'-diphosphate (10 μM). The antiplatelet activity of DL-n-butyl 5-hydroxy-N-(2-phenoxypropionyl)anthranilate (9, IC50 = 10.5 μM) was most active among the tested compounds and ethyl ester 8 (IC50 = 11.2 μM) showed the second most activity. DL-Ethyl and DL-n-butyl 5-(p-toluenesulfonyloxy)-N-(2-phenoxypropionyl)anthranilate (12, IC50 = 13.1 μM and 13, IC50 = 14.0 μM), DL-methyl N-(2-phenoxybutyryl)anthranilate (2, IC50 = 12.7 μM), DL-N-(2-phenoxypropionyl)anthranilic acid (5, IC50 = 13.7 μM) displayed lower antiplatelet activity than 8 and 9. Compound 5 was more active than methyl ester prodrug 1. n-Butyl 5-hydroxy-N-(4'-acetoxybenzoyl)anthranilate (15, IC50 = 28.3 μM) showed moderate activity. Compounds 1 (IC50 = 42.8 μM), 4 (IC50 = 56.7 μM), 16 (IC50 = 51.0 μM), and 17 (IC50 = 49.8 μM) exhibited low antiplatelet activity. Methyl N-phenoxyacetylanthranilate (3, IC50 = 78.0 μM) showed the lowest antiplatelet activity. The compounds with branched alkyl chain (2 and 5) were more active than compounds with straight chain (3 and 4). The apparent permeability coefficient (Papp, cm/s) values of compounds 2 and 9 were determined as 45.34 ± 4.67 and 33.17 ± 5.15 × 10(-6) cm/s by Caco-2 cell permeability assay.
authors.affiliation: College of Pharmacy, Catholic University of Daegu, 712-702, Hayangro 13-13, Gyeongsan, 712-702, Korea.
authors.forename: Sohee
authors.initials: S
authors.lastname: Kim
authors.forename: Beom Soo
authors.initials: BS
authors.lastname: Shin
authors.forename: Eunsook
authors.initials: E
authors.lastname: Ma
mesh_terms: D000244:Adenosine Diphosphate / Q000494:pharmacology*; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism*; D013329:Structure-Activity Relationship; D062367:ortho-Aminobenzoates / Q000138:chemical synthesis* / Q000378:metabolism*
chemical_list: D010975:Platelet Aggregation Inhibitors; D062367:ortho-Aminobenzoates; D000244:Adenosine Diphosphate; C000219:anthranilamide