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J Med Chem. 2009 Jul 9;52(13):3982-93. doi: 10.1021/jm900364m.

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

Author information

1
Department of Medicinal Chemistry, GlaxoSmithKline, Collegeville, Pennsylvania 19426, USA. Robert.W.Marquis@gsk.com

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.

PMID:
19492813
DOI:
10.1021/jm900364m
[Indexed for MEDLINE]

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