ABSTRACT
We describe the design, synthesis, and evaluation of benzimidazoles as benzamide replacements within a series of trisubstituted cyclohexane CCR2 antagonists. 7-Trifluoromethylbenzimidazoles displayed potent binding and functional antagonism of CCR2 while being selective over CCR3. These benzimidazoles were also incorporated into lactam-containing antagonists, thus completely eliminating the customary bis-amide.
Subject(s)
Benzimidazoles/pharmacology , Cyclohexanes/chemistry , Receptors, CCR2/antagonists & inhibitors , Benzimidazoles/chemical synthesis , Benzimidazoles/chemistry , Dose-Response Relationship, Drug , Drug Design , Humans , Microsomes/drug effects , Molecular Structure , Structure-Activity RelationshipABSTRACT
We describe an isostere-driven approach to improve upon a previously-described series of capped dipeptide antagonists of CC Chemokine Receptor 2 (CCR2). Modification of the substitution around the isostere was combined with additional changes in a distal aromatic substituent to provide single-digit nanomolar antagonists of CCR2. These studies led to the identification of 18, a compound that was suitable for studies in murine models of CCR2 activity.
Subject(s)
Amino Alcohols/chemistry , Receptors, CCR2/antagonists & inhibitors , Amino Alcohols/pharmacology , Animals , Biological Availability , MiceABSTRACT
We describe the design, synthesis, and evaluation, of gamma-lactams as glycinamide replacements within a series of di- and trisubstituted cyclohexane CCR2 antagonists. The lactam-containing trisubstituted cyclohexanes proved to be more potent than the disubstituted analogs, as trisubstituted analog, lactam 13, displayed excellent activity (CCR2 binding IC(50)=1.0 nM and chemotaxis IC(50) = 0.5 nM) and improved metabolic stability over its parent glycinamide.
Subject(s)
Cyclohexanes/pharmacology , Glycine/analogs & derivatives , Lactams/chemistry , Receptors, CCR2/antagonists & inhibitors , Animals , Chemotaxis/drug effects , Cyclohexanes/chemistry , Glycine/chemistry , MiceABSTRACT
Potent sulfone-containing di- and trisubstituted cyclohexanes were synthesized and evaluated as CC chemokine receptor 2 (CCR2) antagonists. This led to the trisubstituted derivative 54, which exhibited excellent binding (CCR2 IC(50)=1.3nM) and functional antagonism (calcium flux IC(50)=0.5nM and chemotaxis IC(50)=0.2nM). The superiority of the trisubstituted scaffold was rationalized to be the result of a conformational rigidification, which provided insight into the bioactive conformation of this chemotype.
Subject(s)
Cyclohexanes/chemical synthesis , Receptors, CCR2/antagonists & inhibitors , Sulfones/chemistry , Cyclohexanes/chemistry , Cyclohexanes/pharmacology , Molecular Conformation , Receptors, CCR2/metabolism , Sulfones/chemical synthesisABSTRACT
A series of trisubstituted cyclohexanes was designed, synthesized and evaluated as CC chemokine receptor 2 (CCR2) antagonists. This led to the identification of two distinct substitution patterns about the cyclohexane ring as potent and selective CCR2 antagonists. Compound 36 exhibited excellent binding (CCR2 IC(50)=2.4 nM) and functional antagonism (calcium flux IC(50)=2.0 nM and chemotaxis IC(50)=5.1 nM).
Subject(s)
Chemistry, Pharmaceutical/methods , Receptors, CCR2/antagonists & inhibitors , Receptors, CCR2/chemistry , Binding Sites , Calcium/chemistry , Chemokine CCL2/chemistry , Chemotaxis , Cyclohexanes/chemistry , Drug Design , Humans , Inhibitory Concentration 50 , Models, Chemical , Molecular Structure , Protein Binding , Structure-Activity RelationshipABSTRACT
A series of cis-3,4-disubstituted piperidines was synthesized and evaluated as CC chemokine receptor 2 (CCR2) antagonists. Compound 24 emerged with an attractive profile, possessing excellent binding (CCR2 IC(50)=3.4 nM) and functional antagonism (calcium flux IC(50)=2.0 nM and chemotaxis IC(50)=5.4 nM). Studies to explore the binding of these piperidine analogs utilized a key CCR2 receptor mutant (E291A) with compound 14 and revealed a significant reliance on Glu291 for binding.
Subject(s)
Glutamic Acid/metabolism , Piperidines/chemical synthesis , Piperidines/pharmacology , Receptors, CCR2/antagonists & inhibitors , Combinatorial Chemistry Techniques , Glutamic Acid/chemistry , Inhibitory Concentration 50 , Molecular Structure , Piperidines/chemistry , Receptors, CCR2/genetics , Stereoisomerism , Structure-Activity RelationshipABSTRACT
We describe the design, synthesis, and evaluation of novel disubstituted cyclohexanes as potent CCR2 antagonists. Exploratory SAR studies led to the cis-disubstituted derivative 22, which displayed excellent binding affinity for CCR2 (binding IC50 = 5.1 nM) and potent functional antagonism (calcium flux IC50 = 18 nM and chemotaxis IC 50 = 1 nM). Site-directed mutagenesis studies with 22 suggest the compound is binding near the key receptor residue Glu291, however, 22 is not reliant on Glu291 for its binding affinity.
Subject(s)
Cyclohexanes/chemical synthesis , Receptors, CCR2/antagonists & inhibitors , Binding, Competitive , Calcium/metabolism , Chemokine CCL2/metabolism , Chemotaxis, Leukocyte/drug effects , Cyclohexanes/chemistry , Cyclohexanes/pharmacology , Humans , In Vitro Techniques , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/metabolism , Models, Molecular , Mutagenesis, Site-Directed , Radioligand Assay , Receptors, CCR2/genetics , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A new series of CCR2 antagonists has been discovered that incorporates intramolecular hydrogen bonding as a strategy for rigidifying the scaffold. The structure-activity relationship was established through initial systematic modification of substitution pattern and chain length, followed by independent optimization of three different substituents (benzylamine, carboxamide, and benzamide). Several of the acyclic compounds display 10-30 nM binding affinity for CCR2. Moreover, these antagonists are able to block both MCP-1-induced Ca(2+) flux and monocyte chemotaxis, and are selective for binding to CCR2 over CCR1 and CCR3.
Subject(s)
Dipeptides/chemical synthesis , Dipeptides/pharmacology , Receptors, CCR2/antagonists & inhibitors , Calcium/metabolism , Chemokine CCL2/antagonists & inhibitors , Chemokine CCL2/pharmacology , Chemotaxis, Leukocyte/drug effects , Hydrogen Bonding , Indicators and Reagents , Molecular Conformation , Monocytes/drug effects , Structure-Activity RelationshipABSTRACT
Based on the realization that N-alkyl 5-arylidene-2-thioxo-1,3-thiazolidin-4-ones are tumor necrosis factor-alpha antagonists, we discovered two additional classes of antagonists: 3-thioxo-2,3-dihydro-1H-imidazo[1,5-a]indol-1-ones (via rational design) and 5-arylidene-2-thioxodihydropyrimidine-4,6(1H,5H)-diones (via computer-guided screening). Chemical modification of the lead structures showed that the structure-activity relationship profiles for both of these series were dependent on the electronic properties of the molecules. Subsequent studies showed that they were light-dependent inhibitors.
