ABSTRACT
The synthesis and structure-activity relationship of a series of 7-azaindole piperidine derivatives are described. SAR studies led to the discovery of the potent CCR2 antagonists displaying IC(50) values in the nanomolar range. The representative compound 15 showed reasonable P450 and pharmacokinetics profile.
Subject(s)
Chemistry, Pharmaceutical/methods , Chemokine CCL2/chemistry , Indoles/chemistry , Piperidines/chemistry , Receptors, CCR2/antagonists & inhibitors , Receptors, CCR2/chemistry , Alcohols/chemistry , Binding Sites , Drug Design , Humans , Inhibitory Concentration 50 , Molecular Structure , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The synthesis and biological evaluation of a series of substituted dipiperidine alcohols are described. Structure-activity relationship studies led to the discovery of potent CCR2 antagonists displaying IC(50) values in the nanomolar or subnanomolar range. The cinnamoyl compounds had higher binding affinities than the corresponding urea analogs.
Subject(s)
Alcohols/pharmacology , Piperidines/pharmacology , Receptors, CCR2/antagonists & inhibitors , Alcohols/chemical synthesis , Alcohols/chemistry , Binding Sites , Drug Evaluation, Preclinical , Humans , Inhibitory Concentration 50 , Molecular Structure , Piperidines/chemical synthesis , Piperidines/chemistry , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A series of substituted dipiperidine compounds have been synthesized and identified as selective CCR2 antagonists. Combining the most favorable substituents led to the discovery of remarkably potent CCR2 antagonists displaying IC50 values in the nanomolar range. Compound 7a had outstanding selectivity over CCR1, CCR3, CCR4, CCR5, CCR6, CCR7, and CCR8 and showed excellent efficacy in adjuvant-induced arthritis model, collagen-induced arthritis model, and allergic asthma model.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Piperidines/chemical synthesis , Receptors, CCR2/antagonists & inhibitors , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Arthritis, Experimental/drug therapy , Asthma/drug therapy , Cell Line , Chemotaxis/drug effects , Crystallography, X-Ray , Humans , Male , Mice , Piperidines/chemistry , Piperidines/pharmacology , Rats , Rats, Inbred Lew , Receptors, CCR2/chemistry , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A series of phenyl piperidine derivatives possessing potent and selective CCR2 antagonist activity is reported. Structure-activity relationship (SAR) studies have established that incorporation of a second ring system adjacent to the aryl piperidine plays an important role in determining the CCR2 potency. Both a second piperidine ring and a 1,3-substituted cyclopentylamine have been probed as linkers. For the cyclopentylamine series, the 1S,3R-configuration exhibits much higher affinity for hCCR2 than the 1R,3S-configuration. Compound 3g shows good selectivity over CCR1, CCR3, 5-HT and has an excellent P450 profile.
Subject(s)
Piperidines/chemical synthesis , Piperidines/pharmacology , Receptors, CCR2/antagonists & inhibitors , Structure-Activity RelationshipABSTRACT
A number of compounds bearing a quaternary ammonium moiety were found to be antagonists with nanomolar binding affinity for the chemokine receptor-2. The structure-activity relationships in the series are described herein along with some detailed characterization of the interesting compounds.
Subject(s)
Anti-Asthmatic Agents/therapeutic use , Asthma/drug therapy , Receptors, Chemokine/antagonists & inhibitors , Humans , Receptors, CCR2ABSTRACT
A novel series of 3,5-diarylisoxazole and 3,5-diaryl-1,2,4-oxadiazole IL-8 inhibitors has been identified. These compounds exhibit activity in an IL-8 binding assay as well as in a functional assay of IL-8 induced elastase release from neutrophils. In addition, one of the compounds exhibits oral activity in a rat adjuvant arthritis model.
Subject(s)
Isoxazoles/chemistry , Isoxazoles/pharmacology , Oxadiazoles/chemistry , Oxadiazoles/pharmacology , Receptors, Interleukin-8A/antagonists & inhibitors , Administration, Oral , Isoxazoles/administration & dosage , Isoxazoles/chemical synthesis , Oxadiazoles/administration & dosage , Oxadiazoles/chemical synthesis , Structure-Activity RelationshipABSTRACT
To investigate the role of phospholipase C (PLC) in inflammatory processes, we tested 1-(6-((17beta-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione (U73122), a widely used PLC inhibitor, in several in vitro and in vivo assays. We first examined the effects of U73122 on human phospholipase C-beta (PLC-beta) isozymes and found that U73122 significantly inhibited recombinant human PLC-beta2, with an IC(50) of approximately 6 microM. U73122 had little effect on PLC-beta1, PLC-beta3, or PLC-beta4. Consistent with its ability to inhibit PLC-beta2 enzymatic activity, U73122 reduced interleukin-8 and leukotriene B(4)-induced Ca(2+) flux and chemotaxis in human neutrophils in a concentration-dependent manner. In vivo, U73122 blocked carrageenan-induced hind paw edema in rats, carrageenan-induced macrophage and lymphocyte accumulation into subcutaneous chambers in dogs, lipopolysaccharide-induced macrophage, lymphocyte infiltration and prostaglandin E(2) production in a mouse peritonitis model, and 12-O-tetradecanoylphorbol-13-acetate-induced ear edema in mice. These results implicate PLC-dependent signaling pathways in the development of acute and chronic inflammatory responses in vivo.
