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Metabolism-guided design of short-acting calcium-sensing receptor antagonists.

Authors
  • Southers, James A
  • Bauman, Jonathan N
  • Price, David A
  • Humphries, Paul S
  • Balan, Gayatri
  • Sagal, John F
  • Maurer, Tristan S
  • Zhang, Yan
  • Oliver, Robert
  • Herr, Michael
  • Healy, David R
  • Li, Mei
  • Kapinos, Brendon
  • Fate, Gwendolyn D
  • Riccardi, Keith A
  • Paralkar, Vishwas M
  • Brown, Thomas A
  • Kalgutkar, Amit S
Type
Published Article
Journal
ACS Medicinal Chemistry Letters
Publisher
American Chemical Society
Publication Date
Aug 12, 2010
Volume
1
Issue
5
Pages
219–223
Identifiers
DOI: 10.1021/ml100058w
PMID: 24900198
Source
Medline
Keywords
License
Unknown

Abstract

As part of a strategy to deliver short-acting calcium-sensing receptor (CaSR) antagonists, the metabolically labile thiomethyl functionality was incorporated into the zwitterionic amino alcohol derivative 3 with the hope of increasing human clearance through oxidative metabolism, while delivering a pharmacologically inactive sulfoxide metabolite. The effort led to the identification of thioanisoles 22 and 23 as potent and orally active CaSR antagonists with a rapid onset of action and short pharmacokinetic half-lives, which led to a rapid and transient stimulation of parathyroid hormone in a dose-dependent fashion following oral administration to rats. On the basis of the balance between target pharmacology, safety, and human disposition profiles, 22 and 23 were advanced as clinical candidates for the treatment of osteoporosis.

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