Antagonists of the Calcium Receptor I. Amino Alcohol-Based Parathyroid Hormone Secretagogues Academic Article uri icon

  •  
  • Overview
  •  
  • Research
  •  
  • Identity
  •  
  • Additional Document Info
  •  
  • View All
  •  

abstract

  • Functional screening of the former SmithKline Beecham compound collection against the human calcium receptor (CaR) resulted in the identification of the amino alcohol-based hit 2 (IC(50) = 11 microM). Structure-activity studies of 2 focused on the optimization of the right- and left-hand side aromatic moieties as well as the amino alcohol linker region. Critical to the optimization of this antagonist template was the discovery that the chirality of the C-2 secondary alcohol played a key role in enhancing both CaR potency as well as selectivity over the beta-adrenergic receptor subtypes. These SAR studies ultimately led to the identification of 38 (NPS 2143; SB-262470A), a potent and orally active CaR antagonist. Pharmacokinetic characterization of 38 in the rat revealed that this molecule had a large volume of distribution (11 L/kg), which resulted in a prolonged systemic exposure, protracted increases in the plasma levels of PTH, and an overall lack of net bone formation effect in a rodent model of osteoporosis.

authors

  • Marquis, Robert W
  • Lago, Amparo M
  • Callahan, James F
  • Trout, Robert E Lee
  • Gowen, Maxine
  • DelMar, Eric G
  • Van Wagenen, Bradford C
  • Logan, Sarah
  • Shimizu, Scott
  • Fox, John
  • Nemeth, Edward F
  • Yang, Zheng
  • Roethke, Theresa
  • Smith, Brian R
  • Ward, Keith W
  • Lee, John
  • Keenan, Richard M
  • Bhatnagar, Pradip

publication date

  • July 9, 2009