title: Lead optimization of isocytosine-derived xanthine oxidase inhibitors.
abstract: We report our attempts at improving the oral efficacy of low-nanomolar inhibitors of xanthine oxidase from isocytosine series through chemical modifications. Our lead compound had earlier shown good in vivo efficacy when administered intraperitoneally but not orally. Several modifications are reported here which achieved more than twofold improvement in exposure. A compound with significant improvement in oral efficacy was also obtained.
authors.affiliation: Department of Medicinal Chemistry, Piramal Healthcare Limited, Goregaon (E), Mumbai 400 063, Maharashtra, India.
authors.forename: Komal
authors.initials: K
authors.lastname: Bajaj
authors.forename: Sandeep
authors.initials: S
authors.lastname: Burudkar
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: Prashant
authors.initials: P
authors.lastname: Tannu
authors.forename: Smriti
authors.initials: S
authors.lastname: Khanna
authors.forename: Ankita
authors.initials: A
authors.lastname: Srivastava
authors.forename: Nitin J
authors.initials: NJ
authors.lastname: Deshmukh
authors.forename: Amol
authors.initials: A
authors.lastname: Dixit
authors.forename: Yogesh
authors.initials: Y
authors.lastname: Ahire
authors.forename: Anagha
authors.initials: A
authors.lastname: Damre
authors.forename: Kumar V S
authors.initials: KV
authors.lastname: Nemmani
authors.forename: Asha
authors.initials: A
authors.lastname: Kulkarni-Almeida
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; D020134:Catalytic Domain; D003596:Cytosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D023421:Models, Animal; D008958:Models, Molecular; D015394:Molecular Structure; D051381:Rats; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; C093270:isocytosine; D003596:Cytosine; D014969:Xanthine Oxidase