ABSTRACT
The identification of a new series of RORc inverse agonists is described. Comprehensive structure-activity relationship studies of this reversed sulfonamide series identified potent RORc inverse agonists in biochemical and cellular assays which were also selective against a panel of nuclear receptors. Our work has contributed a compound that may serve as a useful in vitro tool to delineate the complex biological pathways involved in signalling through RORc. An X-ray co-crystal structure of an analogue with RORc has also provided useful insights into the binding interactions of the new series.
Subject(s)
Nuclear Receptor Subfamily 1, Group F, Member 3/agonists , Sulfonamides/chemistry , Binding Sites , Cell Survival/drug effects , Crystallography, X-Ray , Cytokines/biosynthesis , Drug Inverse Agonism , HEK293 Cells , Humans , Leukocytes, Mononuclear/cytology , Leukocytes, Mononuclear/drug effects , Molecular Dynamics Simulation , Nuclear Receptor Subfamily 1, Group F, Member 3/antagonists & inhibitors , Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism , Protein Binding , Protein Structure, Tertiary , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/toxicityABSTRACT
This report describes the effect of replacing the central basic amine present in many known 5-HT(2A) ligands with an aromatic residue. We targeted the isomeric phenethylpyridines 2 and 3 and these compounds proved to be excellent leads, possessing good 5-HT(2A) receptor binding affinity and selectivity over the 5-HT(2C) subtype. Optimization of one isomer led to the identification of 25, a compound with sub-nanomolar 5-HT(2A) affinity and selectivity over 5-HT(2C) of greater than 4600-fold.
Subject(s)
Chemistry, Pharmaceutical/methods , Pyridines/chemistry , Pyridines/chemical synthesis , Receptor, Serotonin, 5-HT2A/chemistry , Serotonin Antagonists/chemistry , Serotonin Antagonists/chemical synthesis , Animals , Drug Design , Humans , Kinetics , Ligands , Models, Chemical , Molecular Conformation , Pyridines/pharmacology , Rats , Serotonin Antagonists/pharmacology , Sulfones/chemistryABSTRACT
Screening of the Merck compound collection identified 6 as an unusually simple, low molecular weight hit with moderate affinity for GABAA receptors. The structural novelty of 6, compared to our advanced series of GABAA alpha5 inverse agonists, made it an attractive molecule for further exploration. This paper will describe the evolution of 6 into a new series of ligands with nanomolar affinity and functional selectivity for GABAA alpha5 receptor subtypes.
Subject(s)
Pyridazines/chemical synthesis , Receptors, GABA-A/drug effects , Animals , Cell Line , Humans , In Vitro Techniques , Ligands , Male , Mice , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Patch-Clamp Techniques , Protein Subunits/physiology , Pyridazines/pharmacokinetics , Pyridazines/pharmacology , Radioligand Assay , Rats , Rats, Sprague-Dawley , Receptors, GABA-A/physiology , Recombinant Proteins/metabolism , Structure-Activity RelationshipABSTRACT
On the basis of a spirocyclic ether screening lead, a series of acyclic sulfones have been identified as high-affinity, selective 5-HT(2A) receptor antagonists. Bioavailability lacking in the parent, 1-(2-(2,4-difluorophenyl)ethyl)-4-(phenylsulfonyl)piperidine (12), was introduced by using stability toward rat liver microsomes as a predictor of bioavailability. By this means, the 4-cyano- and 4-carboxamidophenylsulfonyl derivatives 26 and 31 were identified as orally bioavailable, brain-penetrant analogues suitable for evaluation in animal models. Bioavailability was also attainable by N substitution leading to the N-phenacyl derivative 35. IKr activity detected through counterscreening was reduced to insignificant levels in vivo with the latter compound.
