title: Structure-based design and biological evaluation of novel 2-(indol-2-yl) thiazole derivatives as xanthine oxidase inhibitors.
abstract: Inhibition of xanthine oxidase (XO) has obviously been a central concept for controlling hyperuricemia, which causes serious and painful inflammatory arthritis disease such as gout. We discovered a series of novel 2-(indol-2-yl)thiazole derivatives as XO inhibitors at the level of nanomolar activity. Structure-guided design using molecular modeling program (Accelrys Software program) provided an excellent basis for optimization of 2-(indol-2-yl)thiazole compounds. Structure-activity relationship indicated that hydrophobic alkoxy group (isopropoxy, cyclopentoxy) at 5-position and hydrogen binding acceptor (NO2, CN) at 7-position of indole ring appear as critical functional groups. Among the compounds, 2-(7-nitro-5-isopropoxy-indol-2-yl)-4-methylthiazole-5-carboxylic acid (9m) exhibits the most potent XO inhibitory activity (IC50 value: 5.1 nM) and the excellent uric acid lowering activity in potassium oxonate induced hyperuricemic rat model.
authors.affiliation: College of Pharmacy, Chungnam National University, Daejeon 305-764, Republic of Korea; Research & Development, LG Life Sciences Ltd., 188 Munji-ro, Yuseong-gu, Daejeon 305-380, Republic of Korea.
authors.forename: Jeong Uk
authors.initials: JU
authors.lastname: Song
authors.affiliation: Research & Development, LG Life Sciences Ltd., 188 Munji-ro, Yuseong-gu, Daejeon 305-380, Republic of Korea.
authors.forename: Jae Wan
authors.initials: JW
authors.lastname: Jang
authors.affiliation: Research & Development, LG Life Sciences Ltd., 188 Munji-ro, Yuseong-gu, Daejeon 305-380, Republic of Korea.
authors.forename: Tae Hun
authors.initials: TH
authors.lastname: Kim
authors.affiliation: Research & Development, LG Life Sciences Ltd., 188 Munji-ro, Yuseong-gu, Daejeon 305-380, Republic of Korea.
authors.forename: Heuisul
authors.initials: H
authors.lastname: Park
authors.affiliation: Research & Development, LG Life Sciences Ltd., 188 Munji-ro, Yuseong-gu, Daejeon 305-380, Republic of Korea.
authors.forename: Wan Su
authors.initials: WS
authors.lastname: Park
authors.affiliation: College of Pharmacy, Chungnam National University, Daejeon 305-764, Republic of Korea. Electronic address: jungshh@cnu.ac.kr.
authors.forename: Sang-Hun
authors.initials: SH
authors.lastname: Jung
authors.affiliation: Research & Development, LG Life Sciences Ltd., 188 Munji-ro, Yuseong-gu, Daejeon 305-380, Republic of Korea. Electronic address: gtakim@lgls.com.
authors.forename: Geun Tae
authors.initials: GT
authors.lastname: Kim
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001665:Binding Sites; D002417:Cattle; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D006207:Half-Life; D033461:Hyperuricemia / Q000188:drug therapy / Q000378:metabolism; D008862:Microsomes, Liver; D062105:Molecular Docking Simulation; D017434:Protein Structure, Tertiary; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D014527:Uric Acid / Q000097:blood; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D013844:Thiazoles; D014527:Uric Acid; D014969:Xanthine Oxidase
keywords: 2-(Indol-2-yl)thiazole; Hyperuricemia; Molecular modeling; Structure–activity relationship; Xanthine oxidase inhibitors