Synthesis and structure-activity relationship of novel RXR antagonists: orally active anti-diabetic and anti-obesity

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Junichi Sakaki1, Masashi Kishida, Kazuhide Konishi

  • 1Novartis Institute for Biomedical Research, Tsukuba Research Institute, Ohkubo 8, Tsukuba-Shi, Ibaraki, Japan.

Bioorganic & Medicinal Chemistry Letters
|July 27, 2007
PubMed

Insights

New diazepinylbenzoic acid derivatives were synthesized and tested. The cyano derivative (16f) demonstrated significant anti-diabetic and anti-obesity effects in mouse models, highlighting its therapeutic potential.

Area of Science:

  • Medicinal Chemistry
  • Pharmacology
  • Endocrinology

Background:

  • Retinoid X Receptor (RXR) plays a crucial role in metabolic regulation.
  • Dysregulation of RXR activity is implicated in diabetes and obesity.
  • Developing novel modulators of RXR is a key therapeutic strategy.

Purpose of the Study:

  • To synthesize and evaluate novel diazepinylbenzoic acid derivatives as inhibitors of RXR transactivation.
  • To assess the anti-diabetic and anti-obesity potential of these compounds in a preclinical model.

Main Methods:

  • Synthesis of a series of diazepinylbenzoic acid derivatives.
  • Inhibition assay to measure the effect on RXR transactivation.
  • In vivo testing of promising compounds in KK-A(y) mice, a model for type 2 diabetes and obesity.

Main Results:

  • Several diazepinylbenzoic acid derivatives were successfully synthesized.
  • The cyano derivative, compound 16f, effectively inhibited RXR transactivation.
  • Oral administration of compound 16f in KK-A(y) mice resulted in significant anti-diabetic and anti-obesity effects.

Conclusions:

  • Diazepinylbenzoic acid derivatives represent a promising class of RXR modulators.
  • Compound 16f exhibits therapeutic potential for managing type 2 diabetes and obesity.
  • Further investigation into the mechanism of action and safety profile of compound 16f is warranted.

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