Lead optimization of isocytosine-derived xanthine oxidase inhibitors

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 report...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2013-02, Vol.23 (3), p.834-838
Hauptverfasser:	Bajaj, Komal, Burudkar, Sandeep, Shah, Pranay, Keche, Ashish, Ghosh, Usha, Tannu, Prashant, Khanna, Smriti, Srivastava, Ankita, Deshmukh, Nitin J., Dixit, Amol, Ahire, Yogesh, Damre, Anagha, Nemmani, Kumar V.S., Kulkarni-Almeida, Asha, B-Rao, Chandrika, Sharma, Rajiv, Sivaramakrishnan, H.
Format:	Artikel
Sprache:	eng
Schlagworte:	Administration, Oral Animals Catalytic Domain chemical derivatives Chemical modification chemistry Cytosine - administration & dosage Cytosine - analogs & derivatives Cytosine - chemistry Cytosine - pharmacology Docking dose response Enzyme Activation - drug effects enzyme inhibitors Enzyme Inhibitors - administration & dosage Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Inhibitory Concentration 50 Isocytosine Lead Models, Animal Models, Molecular Molecular Structure Pharmacokinetics pyrimidines Rats Structure–activity relationship Xanthine oxidase Xanthine Oxidase - antagonists & inhibitors Xanthine oxidase inhibitors
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Zusammenfassung:	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.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2012.11.057