2. Academic Validation
  3. Antagonists of the calcium receptor. 2. Amino alcohol-based parathyroid hormone secretagogues

Antagonists of the calcium receptor. 2. Amino alcohol-based parathyroid hormone secretagogues

  • J Med Chem. 2009 Nov 12;52(21):6599-605. doi: 10.1021/jm900563e.
Robert W Marquis 1,  Amparo M Lago,  James F Callahan,  Attiq Rahman,  Xiaoyang Dong,  George B Stroup,  Sandra Hoffman,  Maxine Gowen,  Eric G DelMar,  Bradford C Van Wagenen,  Sarah Logan,  Scott Shimizu,  John Fox,  Edward F Nemeth,  Theresa Roethke,  Brian R Smith,  Keith W Ward,  Pradip Bhatnagar
Affiliations

Affiliation

  • 1 Department of Medicinal Chemistry, GlaxoSmithKline, Collegeville, Pennsylvania 19426, USA. Robert.W.Marquis@gsk.com
PMID: 19821575 DOI: 10.1021/jm900563e
Abstract

When administered as a single agent to rats, the previously reported calcium receptor antagonist 3 elicited a sustained elevation of plasma PTH resulting in no increase in overall bone mineral density. The lack of a bone building effect for analogue 3 was attributed to the large volume of distribution (V(dss)(rat) = 11 L/kg), producing a protracted plasma PTH profile. Incorporation of a carboxylic acid functionality into the amino alcohol template led to the identification of 12 with a lower volume of distribution (V(dss)(12) = 1.18 L/kg) and a shorter half-life. The zwitterionic nature of antagonist 12 necessitated the utility of an ester prodrug approach to increase overall permeability. Antagonist 12 elicited a rapid and transient increase in circulating levels of PTH following oral dosing of the ester prodrug 11 in the dog. The magnitude and duration of the increases in plasma levels of PTH would be expected to stimulate new bone formation.

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