ABSTRACT
SAR studies were conducted around lead compound 1 using high-throughput parallel solution and solid phase synthesis. Our lead optimization efforts led to the identification of several CCR2b antagonists with potent activity in both binding and functional assays [Compound 71 CCR2b Binding IC(50) 3.2 nM; MCP-1-Induced Chemotaxis IC(50) 0.83 nM; Ca(2+) Flux IC(50) 7.5 nM].
Subject(s)
Chemokine CCL2/metabolism , Chemotaxis/drug effects , Pyrrolidines/pharmacology , Receptors, CCR2/antagonists & inhibitors , Calcium/metabolism , Cells, Cultured , Chromatography, High Pressure Liquid , Fluorescence , Humans , Kidney/cytology , Kidney/drug effects , Kidney/metabolism , Molecular Structure , Monocytes/drug effects , Monocytes/metabolism , Pyrrolidines/chemical synthesis , Receptors, CCR2/metabolism , Structure-Activity Relationship , TransfectionABSTRACT
N,N'-Disubstituted homopiperazine derivatives have been discovered as CC-chemokine receptor 2b (CCR2b) inhibitors with submicromolar activity in the CCR2b binding assay. A 4-substituted benzyl group on one homopiperazine nitrogen was an important moiety for binding affinity to the CCR2b receptor. The SAR for CCR2b binding affinity correlated inversely with the sigma factor of the functional group on this benzyl moiety. Introduction of hydroxy groups to appropriate positions in the 3,3-diphenylpropyl group on the other homopiperazine nitrogen increased CCR2b binding activity. The synthesis of an informer library to search for alternative substructures is also described.
Subject(s)
Piperazines/chemical synthesis , Receptors, Chemokine/antagonists & inhibitors , Cell Line , Chemokine CCL2/metabolism , Combinatorial Chemistry Techniques , Drug Design , Humans , Piperazines/chemistry , Piperazines/pharmacology , Radioligand Assay , Receptors, CCR2 , Structure-Activity RelationshipABSTRACT
Structure-activity relationships (SAR) of a weakly active class of CCR2b inhibitors were utilized to initiate a lead evolution program employing the Drug Discovery Engine. Several alternative structural series have been discovered that display nanomolar activity in the CCR2b binding and CCR2b-mediated chemotaxis assays.
Subject(s)
Diamines/chemical synthesis , Receptors, Chemokine/antagonists & inhibitors , Cell Line , Chemokine CCL2/metabolism , Chemotaxis/drug effects , Combinatorial Chemistry Techniques , Diamines/chemistry , Diamines/pharmacology , Drug Design , Humans , Piperidines/chemical synthesis , Piperidines/chemistry , Piperidines/pharmacology , Pyrrolidines/chemical synthesis , Pyrrolidines/chemistry , Pyrrolidines/pharmacology , Radioligand Assay , Receptors, CCR2 , Structure-Activity RelationshipABSTRACT
We describe a novel asymmetric approach using Staudinger chemistry to proline-derived spiro-beta-lactams. A chiral group at C-4 of the acid chloride of proline directs the stereoselectivity of Staudinger chemistry and later is sacrificed to obtain optically active 5.4-spiro-beta-lactams. The scope, limitations, and mechanistic rationale for the observed results of Staudinger Chemistry of the acid chloride of 4-alkyl(aryl)sulfonyloxy-l-proline with imines are also discussed.
Subject(s)
Proline/chemistry , beta-Lactams/chemical synthesis , Catalysis , Chemistry, Organic/methods , Imines/chemistry , Magnetic Resonance Spectroscopy , Molecular Structure , StereoisomerismABSTRACT
The arylamidrazones have been found to be potent corticotropin releasing factor (CRF) receptor antagonists structurally distinct from previously reported CRF1 antagonists. Attempts to modify the arylamidrazone core suggested an important role for the anilino NH moiety. The right-hand-side 2-nitro feature in lead 1 could be replaced with substituents methyl, chloro, cyano, or trifluoromethyl with a 4- to 10-fold reduction in receptor binding. With appropriate left-hand-side modifications, this potency loss could be recovered.
