Discovery of brain penetrant, soluble, pyrazole amide EP1 receptor antagonists

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.

This letter details the discovery and characterisation of a series of amides and reversed amides as EP1 antagonists. Compounds such as 4h, 4j and 10b displayed good solubility, CNS penetration and in vivo pharmacokinetic parameters but failed to show satisfactory oral exposure.Figure optionsDownload as PowerPoint slide