title: Design, synthesis, and biological evaluation of a series of alkoxy-3-indolylacetic acids as peroxisome proliferator-activated receptor γ/δ agonists.
abstract: A series of alkoxy-3-indolylacetic acid analogs has been discovered as peroxisome proliferator-activated receptor (PPAR) agonists. Structure-activity relationship study indicated that PPARα/γ/δ activities were dependent on the nature of the hydrophobic group, the attachment position of the alkoxy linker to the indole ring, and N-alkylation of indole nitrogen. Some compounds presented significant PPARγ/δ activity and molecular modeling suggested their putative binding modes in the ligand binding domain of PPARγ. Of these, compound 51 was selected for in vivo study via an evaluation of microsomal stability in mouse and human liver. Compound 51 lowered the levels of fasting blood glucose, insulin, and HbA1c without gain in body weight in db/db mice. When compound 51 was treated, hepatic triglycerides level and the size of adipocytes in white adipose tissue of db/db mice were also reduced as opposed to treatment with rosiglitazone. Taken together, compound 51 shows high potential warranting further studies in models for diabetes and related metabolic disorders and may be in use as a chemical tool for the understanding of PPAR biology.
authors.affiliation: Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University, Chengpa-ro 47-gil 100, Yongsan-gu, Seoul 140-742, Republic of Korea.
authors.forename: Hyo Jin
authors.initials: HJ
authors.lastname: Gim
authors.affiliation: Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University, Chengpa-ro 47-gil 100, Yongsan-gu, Seoul 140-742, Republic of Korea.
authors.forename: Hua
authors.initials: H
authors.lastname: Li
authors.affiliation: Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University, Chengpa-ro 47-gil 100, Yongsan-gu, Seoul 140-742, Republic of Korea.
authors.forename: Ji Hye
authors.initials: JH
authors.lastname: Jeong
authors.affiliation: Department of Food and Nutrition, Sookmyung Women's University, Chengpa-ro 47-gil 100, Yongsan-gu, Seoul 140-742, Republic of Korea.
authors.forename: Su Jeong
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Department of Food and Nutrition, Sookmyung Women's University, Chengpa-ro 47-gil 100, Yongsan-gu, Seoul 140-742, Republic of Korea.
authors.forename: Mi-Kyung
authors.initials: MK
authors.lastname: Sung
authors.affiliation: Department of Biochemistry, Chonbuk National University Medical School, Jeonju, Jeonbuk 561-756, Republic of Korea.
authors.forename: Mi-Young
authors.initials: MY
authors.lastname: Song
authors.affiliation: Department of Biochemistry, Chonbuk National University Medical School, Jeonju, Jeonbuk 561-756, Republic of Korea.
authors.forename: Byung-Hyun
authors.initials: BH
authors.lastname: Park
authors.affiliation: Bio-Evaluation Center, Korea Research Institute Bioscience and Biotechnology (KRIBB), Ochang, Chungbuk 363-833, Republic of Korea.
authors.forename: Soo Jin
authors.initials: SJ
authors.lastname: Oh
authors.affiliation: Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University, Chengpa-ro 47-gil 100, Yongsan-gu, Seoul 140-742, Republic of Korea.
authors.forename: Jae-Ha
authors.initials: JH
authors.lastname: Ryu
authors.affiliation: Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University, Chengpa-ro 47-gil 100, Yongsan-gu, Seoul 140-742, Republic of Korea. Electronic address: rjeon@sookmyung.ac.kr.
authors.forename: Raok
authors.initials: R
authors.lastname: Jeon
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D052436:Adipose Tissue, White / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000438:Alcohols / Q000737:chemistry*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015195:Drug Design; D005215:Fasting; D005786:Gene Expression Regulation; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D007210:Indoleacetic Acids / Q000138:chemical synthesis / Q000494:pharmacology*; D007328:Insulin / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D047494:PPAR delta / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D000077154:Rosiglitazone; D015398:Signal Transduction; D045162:Thiazolidinediones / Q000494:pharmacology
chemical_list: D000438:Alcohols; D001786:Blood Glucose; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007210:Indoleacetic Acids; D007328:Insulin; D047494:PPAR delta; D047495:PPAR gamma; D000077154:Rosiglitazone; D045162:Thiazolidinediones; C059688:alkoxyl radical
keywords: Agonist; Indolylacetic acid; Metabolic disease; PPAR