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.
Subject(s)
Brain/drug effects , Central Nervous System/drug effects , Pyrazoles/chemistry , Receptors, Prostaglandin E/antagonists & inhibitors , Amides/chemistry , Carboxylic Acids/chemistry , Chemistry, Pharmaceutical/methods , Drug Design , Humans , Inhibitory Concentration 50 , Isoquinolines/chemistry , Models, Chemical , Molecular Structure , Receptors, Prostaglandin E, EP1 Subtype , Solubility , Structure-Activity RelationshipABSTRACT
Replacement of the carboxylic acid group in a series of previously described methylene-linked pyrazole EP(1) receptor antagonists led to the discovery of amide, reversed amide and carbamate derivatives. Two compounds, 10a and 10b, were identified as brain penetrant compounds and both demonstrated efficacy in the CFA model of inflammatory pain.
Subject(s)
Analgesics/chemical synthesis , Analgesics/pharmacology , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Receptors, Prostaglandin E/antagonists & inhibitors , Analgesics/chemistry , Animals , Brain/drug effects , Central Nervous System/drug effects , Combinatorial Chemistry Techniques , Disease Models, Animal , Dose-Response Relationship, Drug , Molecular Structure , Pain Measurement , Pyrazoles/chemistry , Rats , Receptors, Prostaglandin E, EP1 Subtype , Structure-Activity RelationshipABSTRACT
High throughput screening combined with efficient datamining and parallel synthesis led to the discovery of a novel series of indolines showing potent in vitro ghrelin receptor agonist activity and acceleration of gastric emptying in rats.
