RESUMEN

Few reported inhibitors of secretory phospholipase A(2) enzymes truly inhibit the IIa human isoform (hnpsPLA(2)-IIa) noncovalently at submicromolar concentrations. Herein, the simple chiral precursor D-tyrosine was derivatised to give a series of potent new inhibitors of hnpsPLA(2)-IIa. A 2.2-A crystal structure shows an inhibitor bound in the active site of the enzyme, chelated to a Ca(2+) ion through carboxylate and amide oxygen atoms, H-bonded through an amide NH group to His48, with multiple hydrophobic contacts and a T-shaped aromatic-group-His6 interaction. Antiinflammatory activity is also demonstrated for two compounds administered orally to rats.

Asunto(s)

Inhibidores Enzimáticos/farmacología , Inflamación/tratamiento farmacológico , Fosfolipasas A/antagonistas & inhibidores , Fosfolipasas A/farmacología , Tirosina/síntesis química , Animales , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/prevención & control , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/química , Humanos , Inflamación/inducido químicamente , Inflamación/prevención & control , Fosfolipasas A2 , Ratas , Ratas Wistar , Relación Estructura-Actividad , Tirosina/farmacocinética