Lead optimization of isocytosine-derived xanthine oxidase inhibitors

Komal Bajaj; Sandeep Burudkar; Pranay Shah; Ashish Keche; Usha Ghosh; Prashant Tannu; Smriti Khanna; Ankita Srivastava; Nitin J Deshmukh; Amol Dixit; Yogesh Ahire; Anagha Damre; Kumar V S Nemmani; Asha Kulkarni-Almeida; Chandrika B-Rao; Rajiv Sharma; H Sivaramakrishnan

doi:10.1016/j.bmcl.2012.11.057

Lead optimization of isocytosine-derived xanthine oxidase inhibitors

Bioorg Med Chem Lett. 2013 Feb 1;23(3):834-8. doi: 10.1016/j.bmcl.2012.11.057. Epub 2012 Nov 29.

Authors

Komal Bajaj¹, Sandeep Burudkar, Pranay Shah, Ashish Keche, Usha Ghosh, Prashant Tannu, Smriti Khanna, Ankita Srivastava, Nitin J Deshmukh, Amol Dixit, Yogesh Ahire, Anagha Damre, Kumar V S Nemmani, Asha Kulkarni-Almeida, Chandrika B-Rao, Rajiv Sharma, H Sivaramakrishnan

Affiliation

¹ Department of Medicinal Chemistry, Piramal Healthcare Limited, Goregaon (E), Mumbai 400 063, Maharashtra, India.

PMID: 23265878
DOI: 10.1016/j.bmcl.2012.11.057

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.

MeSH terms

Administration, Oral
Animals
Catalytic Domain
Cytosine / administration & dosage
Cytosine / analogs & derivatives*
Cytosine / chemistry
Cytosine / pharmacology
Enzyme Activation / drug effects
Enzyme Inhibitors / administration & dosage
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / pharmacology
Inhibitory Concentration 50
Models, Animal
Models, Molecular
Molecular Structure
Rats
Xanthine Oxidase / antagonists & inhibitors*

Substances

Enzyme Inhibitors
isocytosine
Cytosine
Xanthine Oxidase