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

被引：47

作者：

Khanna, Smriti ^{[1
]}

Burudkar, Sandeep ^{[2
]}

Bajaj, Komal ^{[2
]}

Shah, Pranay ^{[2
]}

Keche, Ashish ^{[2
]}

Ghosh, Usha ^{[2
]}

Desai, Avani ^{[3
]}

Srivastava, Ankita ^{[3
]}

Kulkarni-Almeida, Asha ^{[3
]}

Deshmukh, Nitin J. ^{[4
]}

Dixit, Amol ^{[4
]}

Brahma, Manoja K. ^{[4
]}

Bahirat, Umakant ^{[4
]}

Doshi, Lalit ^{[4
]}

Nemmani, Kumar V. S. ^{[4
]}

Tannu, Prashant ^{[5
]}

Damre, Anagha ^{[5
]}

B-Rao, Chandrika ^{[1
]}

Sharma, Rajiv ^{[2
]}

Sivaramakrishnan, H. ^{[2
]}

机构：

[1] Piramal Healthcare Ltd, Discovery Informat, Bombay 400063, Maharashtra, India

[2] Piramal Healthcare Ltd, Dept Med Chem, Bombay 400063, Maharashtra, India

[3] Piramal Healthcare Ltd, Dept High Throughput Screening & Biotechnol, Bombay 400063, Maharashtra, India

[4] Piramal Healthcare Ltd, Dept Pharmacol, Bombay 400063, Maharashtra, India

[5] Piramal Healthcare Ltd, Dept Drug Metab & Pharmacokinet, Bombay 400063, Maharashtra, India

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2012年 / 22卷 / 24期

关键词：

Xanthine oxidase inhibitors; Isocytosine; Structure-activity relationship; Docking; Lead optimization; DISCOVERY;

D O I：

10.1016/j.bmcl.2012.10.029

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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. (C) 2012 Elsevier Ltd. All rights reserved.

引用

页码：7543 / 7546

页数：4