Source:http://linkedlifedata.com/resource/pubmed/id/19492813
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
13
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| pubmed:dateCreated |
2009-7-2
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| pubmed:abstractText |
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.
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| pubmed:language |
eng
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| pubmed:journal | |
| pubmed:citationSubset |
IM
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| pubmed:chemical | |
| pubmed:status |
MEDLINE
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| pubmed:month |
Jul
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| pubmed:issn |
1520-4804
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| pubmed:author |
pubmed-author:BhatnagarPradipP,
pubmed-author:CallahanJames FJF,
pubmed-author:DelMarEric GEG,
pubmed-author:FoxJohnJ,
pubmed-author:GowenMaxineM,
pubmed-author:KeenanRichard MRM,
pubmed-author:LagoAmparo MAM,
pubmed-author:LeeJohnJ,
pubmed-author:LoganSarahS,
pubmed-author:MarquisRobert WRW,
pubmed-author:NemethEdward FEF,
pubmed-author:RoethkeTheresaT,
pubmed-author:ShimizuScottS,
pubmed-author:SmithBrian RBR,
pubmed-author:TroutRobert E LeeRE,
pubmed-author:Van WagenenBradford CBC,
pubmed-author:WardKeith WKW,
pubmed-author:YangZhengZ
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| pubmed:issnType |
Electronic
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| pubmed:day |
9
|
| pubmed:volume |
52
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
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| pubmed:pagination |
3982-93
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| pubmed:meshHeading |
pubmed-meshheading:19492813-Administration, Oral,
pubmed-meshheading:19492813-Amino Alcohols,
pubmed-meshheading:19492813-Animals,
pubmed-meshheading:19492813-Humans,
pubmed-meshheading:19492813-Osteoporosis,
pubmed-meshheading:19492813-Parathyroid Hormone,
pubmed-meshheading:19492813-Rats,
pubmed-meshheading:19492813-Receptors, Calcium-Sensing,
pubmed-meshheading:19492813-Structure-Activity Relationship,
pubmed-meshheading:19492813-Tissue Distribution
|
| pubmed:year |
2009
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| pubmed:articleTitle |
Antagonists of the calcium receptor I. Amino alcohol-based parathyroid hormone secretagogues.
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| pubmed:affiliation |
Department of Medicinal Chemistry, GlaxoSmithKline, Collegeville, Pennsylvania 19426, USA. Robert.W.Marquis@gsk.com
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| pubmed:publicationType |
Journal Article
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