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Discovery of brain penetrant, soluble, pyrazole amide EP1 receptor antagonists |
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| Authors: | Hall Adrian Billinton Andy Bristow Alan K Brown Susan H Chowdhury Anita Cutler Leanne Giblin Gerard M P Goldsmith Paul Hayhow Thomas G Kilford Ian R Naylor Alan Passingham Barry Rawlings D Anthony |
| Affiliation: | aNeurolosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK;bPharmaceutical Development, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK |
| Abstract: | We describe the discovery of a series of pyrazole amide EP1 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. |
| Keywords: | Non-acidic EP1 antagonist Amide EP1 antagonist Brain penetration CNS penetration Solubility Improved solubility Oral exposure Oral absorption |
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