ABSTRACT
Through the application of TRAP (target-related affinity profiling), we identified a novel class of heteroaroylphenylureas that inhibit human CCL2-induced chemotaxis of monocytes/macrophages both in vitro and in vivo. This inhibition was concentration-dependent and selective with regard to other chemokines. The compounds, however, did not antagonize the binding of (125)I-labeled CCL2 to the CCR2 receptor nor did they block CCR2-mediated signal transduction responses such as calcium mobilization. Optimization of early leads for potency and pharmacokinetic parameters resulted in the identification of 17, a potent inhibitor of chemotaxis (IC(50) = 80 nM) with excellent oral bioavailability in rats (F = 60%). Compound 17 reduced swelling and joint destruction in two rat models of rheumatoid arthritis and delayed disease onset and produced near complete resolution of symptoms in a mouse model of multiple sclerosis.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Chemokine CCL2/antagonists & inhibitors , Phenylurea Compounds/chemical synthesis , Administration, Oral , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Arthritis, Experimental/drug therapy , Arthritis, Experimental/pathology , Arthritis, Rheumatoid/drug therapy , Arthritis, Rheumatoid/pathology , Biological Availability , Bridged Bicyclo Compounds, Heterocyclic/pharmacokinetics , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , CHO Cells , Cell Line, Tumor , Chemotaxis/drug effects , Cricetinae , Cricetulus , Humans , Joints/drug effects , Joints/pathology , Macrophages/drug effects , Macrophages/physiology , Mice , Mice, Inbred ICR , Monocytes/drug effects , Monocytes/physiology , Multiple Sclerosis/drug therapy , Phenylurea Compounds/pharmacokinetics , Phenylurea Compounds/pharmacology , Radioligand Assay , Rats , Receptors, CCR2/metabolism , Structure-Activity RelationshipABSTRACT
In this Letter, we describe our efforts to design HEA BACE-1 inhibitors that are highly permeable coupled with negligible levels of permeability-glycoprotein activity. These efforts culminate in producing 16 which lowers Αß by 28% and 32% in the cortex and CSF, respectively, in the preclinical wild type Hartley guinea pig animal model when dosed orally at 30mpk BID for 2.5days.
