Antagonists of the Calcium Receptor I. Amino Alcohol-Based Parathyroid Hormone Secretagogues

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 (IC50 = 11 μM). Structure−activity studies of 2 focused on the optimization of the right- and left-hand side aromatic moi...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2009-07, Vol.52 (13), p.3982-3993
Main 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
Format: Article
Language:English
Subjects:
Administration, Oral
Amino Alcohols - chemistry
Amino Alcohols - pharmacokinetics
Animals
Biological and medical sciences
Bones, joints and connective tissue. Antiinflammatory agents
Humans
Medical sciences
Osteoporosis - drug therapy
Parathyroid Hormone - blood
Pharmacology. Drug treatments
Rats
Receptors, Calcium-Sensing - antagonists & inhibitors
Structure-Activity Relationship
Tissue Distribution
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Summary: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 (IC50 = 11 μM). 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 β-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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm900364m