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Synthesis and evaluation of thiomannosides,potent and orally active FimH inhibitors |
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| Authors: | Jitendra A Sattigeri Malvika Garg Pragya Bhateja Ajay Soni Abdul Rehman Abdul Rauf Mahendrakumar Gupta Mahesh S Deshmukh Tarun Jain Nidhi Alekar Tarani Kanta Barman Paras Jha Tridib Chaira Ramesh B Bambal Dilip J Upadhyay Takahide Nishi |
| Institution: | 1. Daiichi Sankyo India Pharma Pvt Ltd., Village Sarhaul, Sector 18, Udyog Vihar Industrial Area, Gurugram 122015, Haryana, India;2. Daiichi Sankyo RD Novare Co., Ltd., 1-16-13, Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan |
| Abstract: | FimH is a type I fimbrial lectin located at the tip of type-1 pili of Gram-negative uropathogenic Escherichia coli (UPEC) guiding its ability to adhere and infect urothelial cells. Accordingly, blocking FimH with small molecule inhibitor is considered as a promising new therapeutic alternative to treat urinary tract infections caused by UPEC. Herein, we report that compounds having the S-glycosidic bond (thiomannosides) had improved metabolic stability and plasma exposures when dosed orally. Especially compound 5h showed the potential to inhibit biofilm formation and also to disrupt the preformed biofilm. And compound 5h showed prophylactic effect in UTI model in mice. |
| Keywords: | Thiomannoside FimH inhibitor Urinary tract infection |
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