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Effect of SI-591, a new class of cathepsin K inhibitor with peptidomimetic structure, on bone metabolism in vitro and in vivo.

Abstract
SI-591[N-[1-[[[(1S)-3-[[(3S)-hexahydro-2-oxo-1H-azepin-3-yl]amino]-1-(1-methylethyl)-2,3-dioxopropyl]amino]carbonyl]cyclohexyl]-2-furancarboxamide] is an orally bioavailable compound that was synthesized as one of several unique peptidomimetic compounds without a basic group. This compound was found to have the ability to inhibit cathepsin K, a lysosomal cysteine protease. Cathepsin K is known to be expressed in osteoclasts and involved in bone loss processes. In this study, SI-591 was shown to inhibit the activity of various purified cathepsin molecules at nanomolar concentrations but had high selectivity for cathepsin K over other subtypes including B and L. SI-591 also decreased the level of CTX-I, a bone resorption marker, which was released from osteoclasts in vitro in a dose-dependent manner. The mobilization of calcium from the bones to the blood stream is known to increase in rats fed with a low calcium diet; SI-591 inhibited this increase in serum calcium level at an oral dose of 3mg/kg. Furthermore, SI-591 significantly decreased the level of CTX-I and DPD, bone resorption markers, at oral doses of 10mg/kg or less in ovariectomized rats, while it did not affect the level of BGP, a bone formation marker. In addition, SI-591 prevented bone mineral density loss in the lumber vertebrae and femurs in ovariectomized rats. These results suggest that SI-591 inhibits bone resorption without affecting osteoblast maturation. Therefore, SI-591, a novel cathepsin K inhibitor, could be a promising agent for the treatment of postmenopausal osteoporosis.
AuthorsToshiaki Fujii, Mizuho Ishikawa, Akiko Kubo, Yoshitaka Tanaka
JournalBone (Bone) Vol. 81 Pg. 427-434 (Dec 2015) ISSN: 1873-2763 [Electronic] United States
PMID26297834 (Publication Type: Journal Article)
CopyrightCopyright © 2015. Published by Elsevier Inc.
Chemical References
  • Azepines
  • Collagen Type I
  • Cysteine Proteinase Inhibitors
  • Dipeptides
  • Peptides
  • Peptidomimetics
  • Recombinant Proteins
  • SI-591
  • collagen type I trimeric cross-linked peptide
  • Cathepsin K
  • Calcium
Topics
  • Administration, Oral
  • Animal Feed
  • Animals
  • Azepines (pharmacology)
  • Bone Density
  • Bone Resorption
  • Bone and Bones (diagnostic imaging, drug effects, metabolism)
  • Calcium (chemistry)
  • Cathepsin K (antagonists & inhibitors)
  • Collagen Type I (chemistry)
  • Cysteine Proteinase Inhibitors (pharmacology)
  • Dipeptides (pharmacology)
  • Female
  • Humans
  • Lumbar Vertebrae (diagnostic imaging, drug effects)
  • Male
  • Osteoclasts (drug effects, metabolism)
  • Osteoporosis, Postmenopausal (drug therapy)
  • Ovariectomy
  • Peptides (chemistry)
  • Peptidomimetics (chemistry)
  • Radiography
  • Rats
  • Rats, Inbred F344
  • Rats, Sprague-Dawley
  • Rats, Wistar
  • Recombinant Proteins (chemistry)

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