Design, synthesis, and biological evaluation of a series of alkoxy-3-indolylacetic acids as peroxisome proliferator-activated receptor γ/δ agonists

Hyo Jin Gim; Hua Li; Ji Hye Jeong; Su Jeong Lee; Mi-Kyung Sung; Mi-Young Song; Byung-Hyun Park; Soo Jin Oh; Jae-Ha Ryu; Raok Jeon

doi:10.1016/j.bmc.2015.04.046

Design, synthesis, and biological evaluation of a series of alkoxy-3-indolylacetic acids as peroxisome proliferator-activated receptor γ/δ agonists

Bioorg Med Chem. 2015 Jul 1;23(13):3322-36. doi: 10.1016/j.bmc.2015.04.046. Epub 2015 Apr 23.

Authors

Affiliations

¹ 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.
² Department of Food and Nutrition, Sookmyung Women's University, Chengpa-ro 47-gil 100, Yongsan-gu, Seoul 140-742, Republic of Korea.
³ Department of Biochemistry, Chonbuk National University Medical School, Jeonju, Jeonbuk 561-756, Republic of Korea.
⁴ Bio-Evaluation Center, Korea Research Institute Bioscience and Biotechnology (KRIBB), Ochang, Chungbuk 363-833, Republic of Korea.
⁵ 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: [email protected].

PMID: 25982078
DOI: 10.1016/j.bmc.2015.04.046

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.

Keywords: Agonist; Indolylacetic acid; Metabolic disease; PPAR.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adipocytes / drug effects
Adipocytes / metabolism
Adipocytes / pathology
Adipose Tissue, White / drug effects
Adipose Tissue, White / metabolism
Adipose Tissue, White / pathology
Alcohols / chemistry*
Animals
Blood Glucose / metabolism
Diabetes Mellitus, Experimental / drug therapy*
Diabetes Mellitus, Experimental / genetics
Diabetes Mellitus, Experimental / metabolism
Diabetes Mellitus, Experimental / pathology
Drug Design
Fasting
Gene Expression Regulation
Glycated Hemoglobin / metabolism
Humans
Hypoglycemic Agents / chemical synthesis
Hypoglycemic Agents / pharmacology*
Indoleacetic Acids / chemical synthesis
Indoleacetic Acids / pharmacology*
Insulin / blood
Liver / drug effects
Liver / metabolism
Liver / pathology
Male
Mice
Microsomes, Liver / drug effects
Microsomes, Liver / metabolism
Microsomes, Liver / pathology
PPAR delta / agonists*
PPAR delta / genetics
PPAR delta / metabolism
PPAR gamma / agonists*
PPAR gamma / genetics
PPAR gamma / metabolism
Rosiglitazone
Signal Transduction
Thiazolidinediones / pharmacology

Substances

Alcohols
Blood Glucose
Glycated Hemoglobin A
Hypoglycemic Agents
Indoleacetic Acids
Insulin
PPAR delta
PPAR gamma
Thiazolidinediones
alkoxyl radical
Rosiglitazone