Discovery of brain penetrant, soluble, pyrazole amide EP sub(1) receptor antagonists

We describe the discovery of a series of pyrazole amide EP sub(1) receptor antagonists with good aqueous solubility and CNS penetration. In order to achieve solubility we investigated the incorporation of a basic group in the region of the molecule previously occupied by a carboxylic acid, which was...

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Published inBioorganic & medicinal chemistry Vol. 18; no. 14; pp. 4027 - 4032
Main Authors Hall, Adrian, Billinton, Andy, Bristow, Alan K, Brown, Susan H, Chowdhury, Anita, Cutler, Leanne, Giblin, Gerard MP, Goldsmith, Paul, Hayhow, Thomas G, Kilford, Ian R, Naylor, Alan, Passingham, Barry, Rawlings, DAnthony
Format Journal Article
LanguageEnglish
Published 01.07.2008
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Summary:We describe the discovery of a series of pyrazole amide EP sub(1) receptor antagonists with good aqueous solubility and CNS penetration. In order to achieve solubility we investigated the incorporation of a basic group in the region of the molecule previously occupied by a carboxylic acid, which was known to be a key element of the pharmacophore. This study led to the identification of compounds such as 4h, 4j and 10b which demonstrated brain-to-blood ratios of 0.8:1-2.0:1 in addition to good solubility and metabolic stability.
Bibliography:ObjectType-Article-1
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ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmcl.2008.05.118