ABSTRACT
Monocyclic and bicyclic ring systems were investigated as the "core" section of a series of diphenylsulphone-containing acetic acid CRTh2 receptor antagonists. A range of potencies were observed and single-digit nanomolar potencies were obtained in both the monocyclic and bicyclic cores. Residence times for the monocyclic compounds were very short. Some of the bicyclic cores displayed better residence times. A methyl group in the northern part of the core, between the head and tail was a necessary requirement for the beginnings of long residence times. Variations of the tail substitution maximised potencies and residence times.
Subject(s)
Receptors, Immunologic/antagonists & inhibitors , Receptors, Prostaglandin/antagonists & inhibitors , Sulfones/chemistry , Sulfones/pharmacology , Dose-Response Relationship, Drug , Humans , Kinetics , Molecular Structure , Structure-Activity Relationship , Sulfones/chemical synthesisABSTRACT
Pyrrolopiperidinone acetic acids (PPAs) were identified as highly potent CRTh2 receptor antagonists. In addition, many of these compounds displayed slow-dissociation kinetics from the receptor. Structure-kinetic relationship (SKR) studies allowed optimisation of the kinetics to give potent analogues with long receptor residence half-lives of up to 23 h. Low permeability was a general feature of this series, however oral bioavailability could be achieved through the use of ester prodrugs.
Subject(s)
Acetates/chemistry , Acetates/pharmacology , Piperidines/chemistry , Pyrazoles/chemistry , Receptors, Immunologic/antagonists & inhibitors , Receptors, Prostaglandin/antagonists & inhibitors , Acetates/chemical synthesis , Acetates/pharmacokinetics , Administration, Oral , Animals , Caco-2 Cells , Cell Membrane Permeability/drug effects , Half-Life , Humans , Rats , Receptors, Immunologic/metabolism , Receptors, Prostaglandin/metabolism , Structure-Activity RelationshipABSTRACT
The correct positioning and orientation of an hydrogen bond acceptor (HBA) in the tail portion of the biaryl series of CRTh2 antagonists is a requirement for long receptor residence time. The HBA in combination with a small steric substituent in the core section (R(core) ≠ H) gives access to compounds with dissociation half-lives of ⩾ 24h.
Subject(s)
Acetates/chemistry , Bridged Bicyclo Compounds/chemistry , Receptors, Immunologic/antagonists & inhibitors , Receptors, Prostaglandin/antagonists & inhibitors , Acetates/chemical synthesis , Acetates/pharmacokinetics , Half-Life , Humans , Hydrogen Bonding , Models, Chemical , Receptors, Immunologic/metabolism , Receptors, Prostaglandin/metabolism , Structure-Activity RelationshipABSTRACT
A novel class of potent Syk inhibitors has been developed from rational design. Highly potent aminopyridine derivatives bearing a 4-trifluoromethyl-2-pyridyl motif and represented by compound 13b IC(50): 0.6 nM were identified. Substitution by a 2-pyrazinyl motif and SAR expansion in position 4 of the central core provided diverse potent non-cytotoxic Syk inhibitors showing nanomolar activity inhibiting human mast cell line LAD2 degranulation.
Subject(s)
Aminopyridines/chemistry , Aminopyridines/pharmacology , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Mast Cells/drug effects , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , Binding Sites , Cell Degranulation/drug effects , Cell Line , Humans , Intracellular Signaling Peptides and Proteins/chemistry , Intracellular Signaling Peptides and Proteins/metabolism , Mast Cells/enzymology , Mast Cells/physiology , Molecular Docking Simulation , Protein-Tyrosine Kinases/chemistry , Protein-Tyrosine Kinases/metabolism , Syk KinaseABSTRACT
A series of aminopyrazines as inhibitors of Syk kinase activity and showing inhibition of LAD2 cells degranulation is described. Optimization of the carboxamide motif with aminomethylpiperidines provided high potency inhibiting Syk but low cellular activity. Amides of cis and trans adamantanol showed good inhibitory activity against Syk as well as remarkable activity in LAD2 cells degranulation assay.
Subject(s)
Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyrazines/chemical synthesis , Pyrazines/pharmacology , Adamantane/analogs & derivatives , Adamantane/chemistry , Adamantane/pharmacology , Cell Line, Tumor , Crystallography, X-Ray , Enzyme Activation/drug effects , Enzyme Inhibitors/pharmacology , Humans , Inhibitory Concentration 50 , Molecular Structure , Pyrazines/chemistry , Syk KinaseABSTRACT
Synthesis and applications of two new nonacid degradable linkers as an alternative to the Wang linker for solid-phase synthesis are described. Resin from linker 2 looks superior to linker 1 in terms of yields for both anchoring of the first building block and cleavage and in terms of higher purity of the final product. Use of linker 2 avoids side reactions associated with the use of Wang resin due to an undesired cleavage during final acid treatment.
Subject(s)
Amino Acids/chemistry , Biphenyl Compounds/chemical synthesis , Peptides/chemistry , Polystyrenes/chemistry , Biphenyl Compounds/chemistry , Combinatorial Chemistry Techniques , Molecular StructureABSTRACT
Hydroxyaminolactams have been used as constrained surrogates of the Ser-Leu dipeptide in the synthesis of analogues of the cycloheptapeptide stylostatin 1 (2). The rate of cyclization through formation of the Ile-Pro amide bond allowed us to prove that the valerolactams used induced a turn in the linear precursor. Ring closure at the Pro-Phe amide bond was much quicker and provided access to larger amounts of the target structures, with high purity. The conformation of psi-stylostatin 4 was compared to that of native stylostatin 1 using NMR analysis. The ability of three psi-stylostatins and the native stylostatin 1 to inhibit growth of cancer cell lines was tested. None of the compounds showed activity below 1 microM. A possible relationship between the decrease in activity and the presence of the piperidone Ser-Leu surrogate is considered.
Subject(s)
Antineoplastic Agents/chemical synthesis , Peptides, Cyclic/chemistry , Peptides, Cyclic/chemical synthesis , Piperidones/chemical synthesis , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Division/drug effects , Cell Line, Tumor , Cyclization , Dimethyl Sulfoxide/chemistry , Dipeptides/chemistry , Drug Screening Assays, Antitumor , Hydrogen Bonding , Kinetics , Magnetic Resonance Spectroscopy , Mice , Peptides, Cyclic/pharmacology , Piperidones/chemistry , Piperidones/pharmacology , Protein Conformation , Solvents , Structure-Activity Relationship , TemperatureABSTRACT
A new method of synthesizing the alkaloid aspidospermidine (1), based on building ring E on the pyridocarbazole [ABCD] ring structure, is reported. The preparation of the pyridocarbazole framework of Aspidosperma alkaloids is a new three-step synthetic application of 2-(1,3-dithian-2-yl)indoles. A tandem conjugate addition-alkylation reaction starting from indolyldithiane (4), 3-methylenelactam 6, and EtI yields the adduct 17. Treatment of lactam 17 with DIBALH leads to formation of the naphthyridoindole 18. Compound 18 isomerizes in aqueous AcOH to yield pyridocarbazole 3. Finally, closure of ring E and subsequent reduction of the dithiane ring produces aspidospermidine. Pyridocarbazoles 2 and 10 were prepared as models.
