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 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
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
In this communication we describe the design, synthesis, and evaluation of novel sultam hydroxamates 4 as MMP-2, -9, and -13 inhibitors. Compound 26 was found to be an active inhibitor (MMP-2 IC(50) = 1 nM) with 1000-fold selectivity over MMP-1 and good oral bioavailability (F = 43%) in mouse. An X-ray crystal structure of 26 in MMP-13 confirms the key hydrogen bonds and prime side binding in the active site.
Subject(s)
Hydroxamic Acids/chemical synthesis , Matrix Metalloproteinase Inhibitors , Sulfonamides/chemical synthesis , Administration, Oral , Animals , Biological Availability , Crystallography, X-Ray , Hydroxamic Acids/chemistry , Hydroxamic Acids/pharmacology , Matrix Metalloproteinase 13 , Mice , Models, Molecular , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacologyABSTRACT
Elevated levels of tumor necrosis factor-alpha (TNF-alpha) have been associated with several inflammatory diseases, and therefore, strategies for its suppression have become important targets in drug discovery. Our efforts to suppress TNF-alpha have centered on the inhibition of TNF-alpha converting enzyme (TACE) through the use of hydroxamate inhibitors. Starting from broad-spectrum matrix metalloproteinase (MMP) inhibitors, we have designed and synthesized novel benzothiadiazepines as potent and selective TACE inhibitors. The benzothiadiazepines were synthesized with variation in P1 and P1' in order to effect potency and selectivity. The inhibitors were evaluated versus porcine TACE (pTACE), and the initial selectivity was assessed with counterscreens of MMP-1, -2, and -9. Several potent and selective inhibitors were discovered with compound 41 being the most active against pTACE (K(i) = 5 nM) while still maintaining good selectivity versus the MMP's (at least 75-fold). Most compounds were assessed in the human peripheral blood mononuclear cell assay (PBMC) and the human whole blood assay (WBA) to determine their ability to suppress TNF-alpha. Compound 32 was the most potent compound in the PBMC assay (IC(50) = 0.35 microM), while compound 62 was the most active in the WBA (IC(50) = 1.4 microM).
Subject(s)
Benzodiazepinones/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Hydroxamic Acids/chemical synthesis , Metalloendopeptidases/antagonists & inhibitors , Thiazepines/chemical synthesis , Tumor Necrosis Factor-alpha/antagonists & inhibitors , ADAM Proteins , ADAM17 Protein , Animals , Benzodiazepinones/chemistry , Benzodiazepinones/pharmacology , Blood Proteins/metabolism , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Humans , Hydroxamic Acids/chemistry , Hydroxamic Acids/pharmacology , Leukocytes, Mononuclear/drug effects , Matrix Metalloproteinase Inhibitors , Models, Molecular , Protein Binding , Structure-Activity Relationship , Swine , Thiazepines/chemistry , Thiazepines/pharmacology , Tumor Necrosis Factor-alpha/biosynthesisABSTRACT
Anti-succinate hydroxamates with cyclic P1 motifs were synthesized as aggrecanase inhibitors. The N-methanesulfonyl piperidine 23 and the N-trifluoroacetyl azetidine 26 were the most potent aggrecanase inhibitors both having an IC(50)=3nM while maintaining >100-fold selectivity over MMP-1, -2, and -9. The cyclic moieties were also capable of altering in vivo metabolism, hence delivering low clearance compounds in both rat and dog studies as shown for compound 14.
