ABSTRACT
We report our attempts at improving the oral efficacy of low-nanomolar inhibitors of xanthine oxidase from isocytosine series through chemical modifications. Our lead compound had earlier shown good in vivo efficacy when administered intraperitoneally but not orally. Several modifications are reported here which achieved more than twofold improvement in exposure. A compound with significant improvement in oral efficacy was also obtained.
Subject(s)
Cytosine/analogs & derivatives , Enzyme Inhibitors/chemistry , Xanthine Oxidase/antagonists & inhibitors , Administration, Oral , Animals , Catalytic Domain , Cytosine/administration & dosage , Cytosine/chemistry , Cytosine/pharmacology , Enzyme Activation/drug effects , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/pharmacology , Inhibitory Concentration 50 , Models, Animal , Models, Molecular , Molecular Structure , RatsABSTRACT
Structure-activity relationship studies were carried out for lead generation following structure-guided design approach from an isocytosine scaffold identified earlier for xanthine oxidase inhibition. A 470-fold improvement in in vitro IC(50) was obtained in the process. Five most potent compounds with nanomolar IC(50) values were selected for pharmacokinetics and in vivo experiments. The best compound showed good in vivo activity when administered intraperitoneally but was not active by oral route. The results suggest that improvement in oral exposure could improve the in vivo efficacy of this series.
