title: Design, Synthesis, and Biological Evaluation of Indole Biphenylcarboxylic Acids as PPARγ Antagonists.
abstract: The thiazolidinediones (TZD) typified by rosiglitazone are the only approved therapeutics targeting PPARγ for the treatment of type-2 diabetes (T2DM). Unfortunately, despite robust insulin sensitizing properties, they are accompanied by a number of severe side effects including congestive heart failure, edema, weight gain, and osteoporosis. We recently identified PPARγ antagonists that bind reversibly with high affinity but do not induce transactivation of the receptor, yet they act as insulin sensitizers in mouse models of diabetes (SR1664).1 This Letter details our synthetic exploration around this novel series of PPARγ antagonists based on an N-biphenylmethylindole scaffold. Structure-activity relationship studies led to the identification of compound 46 as a high affinity PPARγ antagonist that exhibits antidiabetic properties following oral administration in diet-induced obese mice.
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida , 130 Scripps Way #A2A, Jupiter, Florida 33458, United States.
authors.forename: Alice
authors.initials: A
authors.lastname: Asteian
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida , 130 Scripps Way #A2A, Jupiter, Florida 33458, United States.
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Blayo
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida , 130 Scripps Way #A2A, Jupiter, Florida 33458, United States.
authors.forename: Yuanjun
authors.initials: Y
authors.lastname: He
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida , 130 Scripps Way #A2A, Jupiter, Florida 33458, United States.
authors.forename: Marcel
authors.initials: M
authors.lastname: Koenig
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida , 130 Scripps Way #A2A, Jupiter, Florida 33458, United States.
authors.forename: Youseung
authors.initials: Y
authors.lastname: Shin
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida , 130 Scripps Way #A2A, Jupiter, Florida 33458, United States.
authors.forename: Dana S
authors.initials: DS
authors.lastname: Kuruvilla
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida , 130 Scripps Way #A2A, Jupiter, Florida 33458, United States.
authors.forename: Cesar A
authors.initials: CA
authors.lastname: Corzo
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida , 130 Scripps Way #A2A, Jupiter, Florida 33458, United States.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Cameron
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida , 130 Scripps Way #A2A, Jupiter, Florida 33458, United States.
authors.forename: Li
authors.initials: L
authors.lastname: Lin
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida , 130 Scripps Way #A2A, Jupiter, Florida 33458, United States.
authors.forename: Claudia
authors.initials: C
authors.lastname: Ruiz
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida , 130 Scripps Way #A2A, Jupiter, Florida 33458, United States.
authors.forename: Susan
authors.initials: S
authors.lastname: Khan
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida , 130 Scripps Way #A2A, Jupiter, Florida 33458, United States.
authors.forename: Naresh
authors.initials: N
authors.lastname: Kumar
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida , 130 Scripps Way #A2A, Jupiter, Florida 33458, United States.
authors.forename: Scott
authors.initials: S
authors.lastname: Busby
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida , 130 Scripps Way #A2A, Jupiter, Florida 33458, United States.
authors.forename: David P
authors.initials: DP
authors.lastname: Marciano
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida , 130 Scripps Way #A2A, Jupiter, Florida 33458, United States.
authors.forename: Ruben D
authors.initials: RD
authors.lastname: Garcia-Ordonez
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida , 130 Scripps Way #A2A, Jupiter, Florida 33458, United States.
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Griffin
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida , 130 Scripps Way #A2A, Jupiter, Florida 33458, United States.
authors.forename: Theodore M
authors.initials: TM
authors.lastname: Kamenecka
keywords: PPARγ; diabetes; indole; nuclear receptor