Author/Authors :
Adrian Hall، نويسنده , , Andy Billinton، نويسنده , , Alan K. Bristow، نويسنده , , Susan H. Brown، نويسنده , , Anita Chowdhury، نويسنده , , Leanne Cutler، نويسنده , , Gerard M.P. Giblin، نويسنده , , Paul Goldsmith، نويسنده , , Thomas G. Hayhow، نويسنده , , Ian R. Kilford، نويسنده , , Alan Naylor، نويسنده , , Barry Passingham، نويسنده , , D. Anthony Rawlings، نويسنده ,
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 :
CNS penetration , Solubility , Oral exposure , Oral absorption , Brain penetration , Non-acidic EP1 antagonist , Amide EP1 antagonist , Improved solubility
