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Updated: Sep 27, 2025

A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators
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A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators

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Pharmacological characterization of AS2690168, a novel small molecule RANKL signal transduction inhibitor

Noriyuki Morikawa1, Yasuko Kato1, Nobuaki Takeshita1

  • 1Drug Discovery Research, Astellas Pharma Inc. 21 Miyukigaoka, Tsukuba, Ibaraki, 305-8585, Japan.

European Journal of Pharmacology
|April 10, 2022
PubMed

Insights

AS2690168 effectively inhibits osteoclastogenesis by targeting the RANKL/RANK pathway. This compound shows promise as a treatment for bone disorders characterized by excessive bone resorption.

Area of Science:

  • Pharmacology
  • Bone Biology
  • Drug Discovery

Background:

  • Pathological osteolysis involves excessive bone resorption by osteoclasts.
  • The RANKL/RANK signaling pathway is crucial for osteoclast differentiation and activation, making it a therapeutic target.
  • AS2690168 was previously identified as an inhibitor of RANKL-induced osteoclastogenesis.

Purpose of the Study:

  • To further characterize the in vitro and in vivo pharmacological profiles of AS2690168.
  • To evaluate AS2690168's efficacy in preclinical models of bone resorption and osteoporosis.

Main Methods:

  • Assessed AS2690168's effect on NFATc1 mRNA expression in RAW264 cells stimulated with soluble RANKL (sRANKL).
  • Determined the IC50 for AS2690168's inhibition of calcium release in parathyroid hormone-stimulated mouse calvaria.
  • Evaluated AS2690168's effects in vivo using sRANKL-induced osteopenic mice, ovariectomized rats, and prednisolone-induced osteoporosis rat models.

Main Results:

  • AS2690168 suppressed sRANKL-induced NFATc1 mRNA expression and calcium release.
  • Oral AS2690168 prevented bone loss in sRANKL-induced osteopenic mice.
  • The compound reduced bone mineral density loss and tartrate-resistant acid phosphatase-5b levels in ovariectomized rats.
  • AS2690168 decreased urine deoxypyridinoline in a rat osteoporosis model.

Conclusions:

  • AS2690168 demonstrates potent inhibitory effects on osteoclastogenesis and bone resorption in vitro and in vivo.
  • These findings support AS2690168 as a promising therapeutic agent for bone disorders involving excessive bone resorption.
Keywords:
InhibitorOsteoporosisRANKL

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