Bioorganic & Medicinal Chemistry Letters 2012-12-15

Isocytosine-based inhibitors of xanthine oxidase: Design, synthesis, SAR, PK and in vivo efficacy in rat model of hyperuricemia

Smriti Khanna, Sandeep Burudkar, Komal Bajaj, Pranay Shah, Ashish Keche, Usha Ghosh, Avani Desai, Ankita Srivastava, Asha Kulkarni-Almeida, Nitin J. Deshmukh, Amol Dixit, Manoja K. Brahma, Umakant Bahirat, Lalit Doshi, Kumar V.S. Nemmani, Prashant Tannu, Anagha Damre, Chandrika B-Rao, Rajiv Sharma, H. Sivaramakrishnan

Index: Bioorg. Med. Chem. Lett. 22(24) , 7543-6, (2012)

Full Text: HTML

Abstract

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.Copyright © 2012 Elsevier Ltd. All rights reserved.