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Isocytosine-based inhibitors of xanthine oxidase: Design,synthesis, SAR,PK and in vivo efficacy in rat model of hyperuricemia |
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| Authors: | 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 VS Nemmani Prashant Tannu Anagha Damre Chandrika B-Rao Rajiv Sharma H Sivaramakrishnan |
| Institution: | 1. Discovery Informatics, Piramal Healthcare Limited, Goregaon (E), Mumbai 400 063, Maharashtra, India;2. Department of Medicinal Chemistry, Piramal Healthcare Limited, Goregaon (E), Mumbai 400 063, Maharashtra, India;3. Department of High Throughput Screening and Biotechnology, Piramal Healthcare Limited, Goregaon (E), Mumbai 400 063, Maharashtra, India;4. Department of Pharmacology, Piramal Healthcare Limited, Goregaon (E), Mumbai 400 063, Maharashtra, India;5. Department of Drug Metabolism and Pharmacokinetics, Piramal Healthcare Limited, Goregaon (E), Mumbai 400 063, Maharashtra, India |
| 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 IC50 was obtained in the process. Five most potent compounds with nanomolar IC50 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. |
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