ABSTRACT
Indazoles are unselectively protected under strongly basic conditions to give a mixture at N-1 and N-2. Under mildly acidic conditions, regioselective protection at N-2 takes place. Thermodynamic conditions lead to regioselective protection at N-1. This trend applies to various substituted indazoles. Protected 5-bromoindazoles participate in Buchwald reactions with a range of amines to generate novel derivatives.
Subject(s)
Amines/chemistry , Indazoles/chemistry , Hydrogen-Ion Concentration , Stereoisomerism , Substrate Specificity , ThermodynamicsABSTRACT
Platelet P2Y12 receptors play a central role in the regulation of platelet function and inhibition of this receptor by treatment with drugs such as clopidogrel results in a reduction of atherothrombotic events. We discovered that modification of natural and synthetic dinucleoside polyphosphates and nucleotides with lipophilic substituents on the ribose and base conferred P2Y12 receptor antagonist properties to these molecules producing potent inhibitors of ADP-mediated platelet aggregation. We describe methods for the preparation of these functionalized dinucleoside polyphosphates and nucleotides and report their associated activities. By analysis of these results and by deconstruction of the necessary structural elements through selected syntheses, we prepared a series of highly functionalized nucleotides, resulting in the selection of an adenosine monophosphate derivative (62) for further clinical development.
Subject(s)
Blood Platelets/metabolism , Membrane Proteins/antagonists & inhibitors , Nucleotides/chemical synthesis , Platelet Aggregation Inhibitors/chemical synthesis , Purinergic P2 Receptor Antagonists , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/chemical synthesis , Adenosine Monophosphate/chemistry , Adenosine Monophosphate/pharmacology , Calcium/metabolism , Cell Line, Tumor , Dinucleoside Phosphates/chemical synthesis , Dinucleoside Phosphates/chemistry , Dinucleoside Phosphates/pharmacology , Humans , In Vitro Techniques , Nucleotides/chemistry , Nucleotides/pharmacology , Platelet Aggregation/drug effects , Platelet Aggregation Inhibitors/chemistry , Platelet Aggregation Inhibitors/pharmacology , Receptors, Purinergic P2Y12 , Structure-Activity RelationshipABSTRACT
Modified adenosine derivatives may lead to the development of P2Y(12) antagonists that are potent, selective, and bind reversibly to the receptor. Analogues of 2',3'-trans-styryl acetal-N6-ureido-adenosine monophosphate were prepared by modification of the 5'-position. The resulting analogues were tested for P2Y(12) antagonism in a platelet aggregation assay.
Subject(s)
Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Membrane Proteins/antagonists & inhibitors , Platelet Aggregation/drug effects , Purinergic P2 Receptor Antagonists , Adenosine Diphosphate/metabolism , Adenosine Monophosphate/chemical synthesis , Adenosine Triphosphate/metabolism , Chromatography, High Pressure Liquid , Humans , Magnetic Resonance Spectroscopy , Molecular Structure , Receptors, Purinergic P2Y12ABSTRACT
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
A strategy for the enantioselective synthesis of trans-2,4-disubstituted piperidines is proposed and applied to the preparation of IS811, a potent CCR3 antagonist. The C2 stereocenter is derived from commercial (R)-epichlorohydrin, while the C4 stereocenter is installed via diastereoselective hydrogenation of an alpha,beta-unsaturated lactone intermediate. Inversion of the original stereocenter via an efficient intramolecular S(N)2 amination affords the piperidine core of IS811. An improved protocol for the lithiation of ethyl propiolate is reported.
Subject(s)
Piperidines/chemical synthesis , Piperidines/pharmacology , Receptors, Chemokine/antagonists & inhibitors , Catalysis , Humans , Hydrogen/chemistry , Molecular Conformation , Piperidines/chemistry , Receptors, CCR3 , StereoisomerismABSTRACT
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
The discovery of novel and selective small molecule antagonists of the CC Chemokine Receptor-3 (CCR3) is presented. Simple conversion from a 4- to 3-benzylpiperidine gave improved selectivity for CCR3 over the serotonin 5HT(2A) receptor. Chiral resolution and exploration of mono- and disubstitution of the N-propylurea resulted in several 3-benzylpiperidine N-propylureas with CCR3 binding IC(50)s under 5 nM. Data from in vitro calcium mobilization and chemotaxis assays for these compounds ranged from high picomolar to low nanomolar EC(50)s and correlated well with antagonist binding IC(50)s.
Subject(s)
Piperidines/metabolism , Receptors, Chemokine/antagonists & inhibitors , Receptors, Chemokine/metabolism , Urea/analogs & derivatives , Urea/metabolism , Animals , CHO Cells , Cattle , Cricetinae , Piperidines/chemistry , Protein Binding/physiology , Receptors, CCR3 , Urea/chemistryABSTRACT
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.
Subject(s)
Anti-Asthmatic Agents/chemistry , Anti-Asthmatic Agents/pharmacology , Receptors, Chemokine/antagonists & inhibitors , Alkylation , Amides/chemistry , Amides/metabolism , Calcium/metabolism , Chemokine CCL11 , Chemokines, CC/metabolism , Chemotaxis, Leukocyte/drug effects , Humans , Inhibitory Concentration 50 , Ligands , Piperidines/chemistry , Receptors, CCR3 , Receptors, Chemokine/chemistry , Receptors, Chemokine/metabolism , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Controlling the elements of planar and axial chirality are the principal challenges in the synthesis of the aglycon of vancomycin. Vancomycin is the prototypical member of the glycopeptide family of antibiotics which are effective for the treatment of infections by methicillin-resistant Staphylococcus aureus. The first total syntheses of the vancomycin and eremomycin aglycons provide insight into the influence of structure on kinetic and thermodynamic control of atropselective macrocyclizations.
