title: Isocytosine-based inhibitors of xanthine oxidase: design, synthesis, SAR, PK and in vivo efficacy in rat model of hyperuricemia.
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.
authors.affiliation: Discovery Informatics, Piramal Healthcare Limited, Goregaon (E), Mumbai 400 063, Maharashtra, India.
authors.forename: Smriti
authors.initials: S
authors.lastname: Khanna
authors.forename: Sandeep
authors.initials: S
authors.lastname: Burudkar
authors.forename: Komal
authors.initials: K
authors.lastname: Bajaj
authors.forename: Pranay
authors.initials: P
authors.lastname: Shah
authors.forename: Ashish
authors.initials: A
authors.lastname: Keche
authors.forename: Usha
authors.initials: U
authors.lastname: Ghosh
authors.forename: Avani
authors.initials: A
authors.lastname: Desai
authors.forename: Ankita
authors.initials: A
authors.lastname: Srivastava
authors.forename: Asha
authors.initials: A
authors.lastname: Kulkarni-Almeida
authors.forename: Nitin J
authors.initials: NJ
authors.lastname: Deshmukh
authors.forename: Amol
authors.initials: A
authors.lastname: Dixit
authors.forename: Manoja K
authors.initials: MK
authors.lastname: Brahma
authors.forename: Umakant
authors.initials: U
authors.lastname: Bahirat
authors.forename: Lalit
authors.initials: L
authors.lastname: Doshi
authors.forename: Kumar V S
authors.initials: KV
authors.lastname: Nemmani
authors.forename: Prashant
authors.initials: P
authors.lastname: Tannu
authors.forename: Anagha
authors.initials: A
authors.lastname: Damre
authors.forename: Chandrika
authors.initials: C
authors.lastname: B-Rao
authors.forename: Rajiv
authors.initials: R
authors.lastname: Sharma
authors.forename: H
authors.initials: H
authors.lastname: Sivaramakrishnan
mesh_terms: D000284:Administration, Oral; D000818:Animals; D003596:Cytosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D033461:Hyperuricemia / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D013997:Time Factors; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; C093270:isocytosine; D003596:Cytosine; D014969:Xanthine Oxidase