title: Design and synthesis of novel 2-(indol-5-yl)thiazole derivatives as xanthine oxidase inhibitors.
abstract: Xanthine oxidase (XO) inhibitors have been widely used for the treatment of gout. Indole rings are frequently used as active scaffold in designing inhibitors for enzymes. Herein, we describe the structure-activity relationship for novel xanthine oxidase inhibitors based on indole scaffold. A series of novel tri-substituted 2-(indol-5-yl)thiazole derivatives were synthesized, and their in vitro inhibitory activities against xanthine oxidase and in vivo efficacy lowering uric acid level in blood were measured. Among them, 2-(3-cyano-2-isopropylindol-5-yl)-4-methylthiazole-5-carboxylic acid exhibits the most potent XO inhibitory activity (IC50 value: 3.5nM) and the excellent plasma uric acid lowering activity. Study of structure activity relationship indicated that hydrophobic moiety (e.g., isopropyl) at 1-position and electron withdrawing group (e.g., CN) at 3-position of indole ring and small hydrophobic group (CH3) at 4-position of the thiazole ring enhanced the XO inhibitory activity. Hydrophobic substitution such as isopropyl at 1-position of the indole moiety without any substitution at 2-position has an essential role for enhancing bioavailability and therefore for high in vivo efficacy.
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: Sung Pil
authors.initials: SP
authors.lastname: Choi
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: Cheol-Kyu
authors.initials: CK
authors.lastname: Jung
authors.affiliation: Research & Development, LG Life Sciences Ltd, 188 Munji-ro, Yuseong-gu, Daejeon 305-380, Republic of Korea.
authors.forename: Joo-Youn
authors.initials: JY
authors.lastname: Lee
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: D000818:Animals; D001665:Binding Sites; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D006207:Half-Life; D057927:Hydrophobic and Hydrophilic Interactions; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D008862:Microsomes, Liver / Q000378:metabolism; D062105:Molecular Docking Simulation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D014527:Uric Acid / Q000037:antagonists & inhibitors / Q000737:chemistry; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C000603770:2-(3-cyano-2-isopropylindol-5-yl)-4-methylthiazole-5-carboxylic acid; D004791:Enzyme Inhibitors; D007211:Indoles; D013844:Thiazoles; D014527:Uric Acid; C030374:indole; D014969:Xanthine Oxidase
keywords: 2-(Indol-5-yl)thiazole; Gout; Hyperuricemia; Xanthine oxidase inhibitors