ABSTRACT
Conformational analysis of the 3-benzylpiperidine in CCR3 antagonist clinical candidate 1 (BMS-639623) predicts that the benzylpiperidine may be replaced by acyclic, conformationally stabilized, anti-1,2-disubstituted phenethyl- and phenpropylamines. Ab initio calculations, enantioselective syntheses, and evaluation in CCR3 binding and chemotaxis assays of anti-1-methyl-2-hydroxyphenethyl- and phenpropylamine-containing CCR3 antagonists support this conformational correlation.
Subject(s)
Piperidines/chemistry , Piperidines/pharmacology , Receptors, CCR3/antagonists & inhibitors , Urea/analogs & derivatives , Cyclization , Hydrogen Bonding , Molecular Conformation , Urea/chemistry , Urea/pharmacologyABSTRACT
Conformational analysis of trans-1,2-disubstituted cyclohexane CCR3 antagonist 2 revealed that the cyclohexane linker could be replaced by an acyclic syn-alpha-methyl-beta-hydroxypropyl linker. Synthesis and biological evaluation of mono- and disubstituted propyl linkers support this conformational correlation. It was also found that the alpha-methyl group to the urea lowered protein binding and that the beta-hydroxyl group lowered affinity for CYP2D6. Ab initio calculations show that the alpha-methyl group governs the spatial orientation of three key functionalities within the molecule. alpha-Methyl-beta-hydroxypropyl urea 31 with a chemotaxis IC(50)=38 pM for eosinophils was chosen to enter clinical development for the treatment of asthma.
Subject(s)
Chemotaxis, Leukocyte/drug effects , Eosinophils/drug effects , Piperidines/pharmacology , Receptors, CCR3/antagonists & inhibitors , Urea/analogs & derivatives , Administration, Oral , Animals , Cytochrome P-450 Enzyme Inhibitors , Dogs , Eosinophils/cytology , Hydrogen Bonding , Mice , Molecular Conformation , Piperidines/chemistry , Piperidines/pharmacokinetics , Rats , Structure-Activity Relationship , Urea/chemistry , Urea/pharmacokinetics , Urea/pharmacologyABSTRACT
DPC168, a benzylpiperidine-substituted aryl urea CCR3 antagonist evaluated in clinical trials, was a relatively potent inhibitor of the 2D6 isoform of cytochrome P-450 (CYP2D6). Replacement of the cyclohexyl central ring with saturated heterocycles provided potent CCR3 antagonists with improved selectivity against CYP2D6. The favorable preclinical profile of DPC168 was maintained in an acetylpiperidine derivative, BMS-570520.
Subject(s)
Benzyl Compounds/chemistry , Benzyl Compounds/pharmacology , Cytochrome P-450 CYP2D6 Inhibitors , Phenylurea Compounds/chemistry , Piperidines/chemistry , Piperidines/pharmacology , Receptors, Chemokine/antagonists & inhibitors , Animals , Benzyl Compounds/chemical synthesis , Biological Assay , Cells, Cultured , Humans , Mice , Pan troglodytes , Phenylurea Compounds/pharmacology , Piperidines/chemical synthesis , Receptors, CCR3 , Structure-Activity RelationshipABSTRACT
Linear unselective CCR3 antagonist leads with IC(50) values in the 200 nM range were converted into low nM binding compounds selective at CCR3 by moving the piperidine nitrogen substituent to the carbon at the 2-position of the ring. Substitution of the piperidine nitrogen with simple alkyl and acyl groups was found to improve the selectivity of this new compound class. In particular, N-{3-[(2S, 4R)-1-(propyl)-4-(4-fluorobenzyl)piperidinyl]propyl}-N'-(3-acetylphenyl)urea exhibited single digit nanomolar IC(50) values for CCR3 with >100-fold selectivity against an extensive counter screen panel.
Subject(s)
Piperidines/chemical synthesis , Piperidines/pharmacology , Receptors, Chemokine/antagonists & inhibitors , Piperidines/chemistry , Receptors, CCR3 , Structure-Activity RelationshipABSTRACT
Starting with our previously described(20) class of CC chemokine receptor-3 (CCR3) antagonist, we improved the potency by replacing the phenyl linker of 1 with a cyclohexyl linker and by replacing the 4-benzylpiperidine with a 3-benzylpiperidine. The resulting compound, 32, is a potent and selective antagonist of CCR3. SAR studies showed that the 3-acetylphenyl urea of 32 could be replaced with heterocyclic ureas or heterocyclic-substituted phenyl ureas and still maintain the potency (inhibition of eotaxin-induced chemotaxis) of this class of compounds in the low-picomolar range (IC(50) = 10-60 pM), representing some of the most potent CCR3 antagonists reported to date. The potency of 32 for mouse CCR3 (chemotaxis IC(50) = 41 nM) and its oral bioavailability in mice (20% F ) were adequate to assess the efficacy in animal models of allergic airway inflammation. Oral administration of 32 reduced eosinophil recruitment into the lungs in a dose-dependent manner in these animal models. On the basis of its overall potency, selectivity, efficacy, and safety profile, the benzenesulfonate salt of 32, designated DPC168, entered phase I clinical trials.
Subject(s)
Cyclohexanes/chemical synthesis , Phenylurea Compounds/chemical synthesis , Piperidines/chemical synthesis , Receptors, Chemokine/antagonists & inhibitors , Animals , Biological Availability , CHO Cells , Caco-2 Cells , Calcium/metabolism , Chemotaxis, Leukocyte/drug effects , Cricetinae , Cyclohexanes/chemistry , Cyclohexanes/pharmacology , Eosinophils/drug effects , Eosinophils/physiology , Female , Humans , Hypersensitivity/drug therapy , Hypersensitivity/immunology , In Vitro Techniques , Inflammation/drug therapy , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Permeability , Phenylurea Compounds/chemistry , Phenylurea Compounds/pharmacology , Piperidines/chemistry , Piperidines/pharmacology , Receptors, CCR3 , Stereoisomerism , Structure-Activity Relationship , Urea/analogs & derivatives , Urea/chemical synthesis , Urea/chemistry , Urea/pharmacologyABSTRACT
The synthesis and structure-activity relationships of N-arylalkylpiperidylmethyl ureas as antagonists of the CC chemokine receptor-3 (CCR3) are presented. These compounds displayed potent binding to the receptor as well as functional antagonism of eotaxin-elicited effects on eosinophils.
Subject(s)
Piperidines/chemical synthesis , Receptors, Chemokine/antagonists & inhibitors , Urea/chemical synthesis , Calcium Signaling/drug effects , Chemokine CCL11 , Chemokines, CC/pharmacology , Drug Interactions , Eosinophils/drug effects , Humans , Inhibitory Concentration 50 , Piperidines/pharmacology , Protein Binding , Receptors, CCR3 , Structure-Activity Relationship , Urea/pharmacologyABSTRACT
Structure-activity relationship (SAR) studies of initial screening hits from our corporate library of compounds and a structurally related series of CCR1 receptor antagonists were used to determine that an N-(alkyl)benzylpiperidine is an essential pharmacophore for selective CCR3 antagonists. Further SAR studies that introduced N-(ureidoalkyl) substituents improved the binding potency of these compounds from the micromolar to the low nanomolar range. This new series of compounds also displays highly potent, in vitro functional CCR3-mediated antagonism of eotaxin-induced Ca(2+) mobilization and chemotaxis of human eosinophils.
Subject(s)
Anti-Allergic Agents/chemical synthesis , Piperidines/chemical synthesis , Receptors, Chemokine/antagonists & inhibitors , Urea/analogs & derivatives , Urea/chemical synthesis , Animals , Anti-Allergic Agents/chemistry , Anti-Allergic Agents/pharmacology , CHO Cells , Calcium/metabolism , Chemokine CCL11 , Chemokines, CC/pharmacology , Chemotaxis, Leukocyte/drug effects , Cricetinae , Eosinophils/cytology , Eosinophils/drug effects , Eosinophils/metabolism , Humans , In Vitro Techniques , Piperidines/chemistry , Piperidines/pharmacology , Receptors, CCR3 , Receptors, Chemokine/metabolism , Structure-Activity Relationship , Urea/chemistry , Urea/pharmacologyABSTRACT
CCR3 antagonist leads with IC(50) values in the microM range were converted into low nM binding compounds that displayed in vitro inhibition of human eosinophil chemotaxis induced by human eotaxin. In particular, 4-benzylpiperidin-1-yl-n-propylureas and erythro-3-(4-benzyl-2-(alpha-hydroxyalkyl)piperidin-1-yl)-n-propylureas (obtained via Beak reaction of N-BOC-4-benzylpiperidine) exhibited single digit nanomolar IC(50) values for CCR3.
