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
We describe the SAR, in terms of heterocyclic replacements, for a series of pyrazole EP(1) receptor antagonists. This study led to the identification of several aromatic heterocyclic replacements for the pyrazole in the original compound. Investigation of replacements for the methylene linker uncovered disparate SAR in the thiazole and pyridine series.
Subject(s)
Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacology , Receptors, Prostaglandin E/antagonists & inhibitors , Models, Molecular , Molecular Structure , Protein Binding , Receptors, Prostaglandin E, EP1 Subtype , Structure-Activity RelationshipABSTRACT
We describe the generation of novel EP(1) receptor antagonists by investigation of thiophene isosteres. In addition, we disclose preliminary in vitro and in vivo DMPK for selected compounds.
Subject(s)
Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacology , Receptors, Prostaglandin E/antagonists & inhibitors , Animals , In Vitro Techniques , Rats , Receptors, Prostaglandin E, EP1 SubtypeABSTRACT
Starting from the tetrapeptide Ac-pYEEI-NHMe and using a structure-based approach, we have designed and synthesised a peptidomimetic ligand for p56(lck) SH2 domain containing a conformationally restricted replacement for the two glutamate residues. We have explored replacments for the isoleucine residue in the pY+3 pocket and thus identified 1-(R)-amino-3-(S)-indaneacetic acid as the most potent replacement. We also report the X-ray crystal structures of two of the antagonists.
