Abstract
We describe the discovery of a series of pyrazole amide EP(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.
MeSH terms
-
Amides / chemistry
-
Brain / drug effects*
-
Carboxylic Acids / chemistry
-
Central Nervous System / drug effects*
-
Chemistry, Pharmaceutical / methods
-
Drug Design
-
Humans
-
Inhibitory Concentration 50
-
Isoquinolines / chemistry
-
Models, Chemical
-
Molecular Structure
-
Pyrazoles / chemistry*
-
Receptors, Prostaglandin E / antagonists & inhibitors*
-
Receptors, Prostaglandin E, EP1 Subtype
-
Solubility
-
Structure-Activity Relationship
Substances
-
Amides
-
Carboxylic Acids
-
Isoquinolines
-
PTGER1 protein, human
-
Pyrazoles
-
Receptors, Prostaglandin E
-
Receptors, Prostaglandin E, EP1 Subtype
-
isoquinoline