ABSTRACT
The synthesis and in vitro binding of several new arginine-containing C3aR ligands are reported. DMPK properties and functional activities of selected compounds have been evaluated. One compound is shown to be active in an in vivo model of airway inflammation after aerosol administration.
Subject(s)
Arginine/pharmacology , Complement Activation/drug effects , Membrane Proteins/metabolism , Receptors, Complement/metabolism , Aerosols/administration & dosage , Animals , Arginine/analogs & derivatives , Arginine/chemical synthesis , Inflammation/chemically induced , Inflammation/pathology , Ligands , Mice , Mice, Inbred BALB C , Models, Biological , Protein Binding , Protein Serine-Threonine Kinases/metabolism , Respiratory Mucosa/pathology , Structure-Activity Relationship , Time FactorsABSTRACT
The synthesis and structure-activity relationships against the C3a receptor of a series of substituted aminopiperidine derivatives are reported. DMPK properties and functional activities of selected compounds are described. The compounds obtained are the first non-arginine ligands of C3aR.
Subject(s)
Amines/chemistry , Complement Activation/drug effects , Membrane Proteins/metabolism , Piperidines/pharmacology , Receptors, Complement/metabolism , Animals , Ligands , Mice , Mice, Inbred BALB C , Piperidines/chemical synthesis , Protein Binding , Protein Serine-Threonine Kinases/metabolism , Structure-Activity RelationshipABSTRACT
Mimics of the benzimidazolone nucleus found in inhibitors of p38 kinase are proposed, and their theoretical potential as bioisosteres is described. A set of calculated descriptors relevant to the anticipated binding interaction for the fragments 1-methyl-1H-benzotriazole 5, 3-methyl-benzo[d]isoxazole 3, and 3-methyl-[1,2,4]triazolo[4,3-a]pyridine 4, pyridine 1, and 1,3-dimethyl-1,3-dihydro-benzoimidazol-2-one 2 are reported. The design considerations and synthesis of p38 inhibitors based on these H-bond acceptor fragments is detailed. Comparative evaluation of the pyridine-, benzimidazolone-, benzotriazole-, and triazolopyridine-based inhibitors shows the triazoles 20 and 25 to be significantly more potent experimentally than the benzimidazolone after which they were modeled. An X-ray crystal structure of 25 bound to the active site shows that the triazole group serves as the H-bond acceptor but unexpectedly as a dual acceptor, inducing movement of the crossover connection of p38alpha. The computed descriptors for the hydrophobic and pi-pi interaction capacities were the most useful in ranking potency.
Subject(s)
Benzimidazoles/chemistry , Pyridines/chemistry , Triazoles/chemistry , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , p38 Mitogen-Activated Protein Kinases/chemistry , Benzimidazoles/chemical synthesis , Binding Sites , Crystallography, X-Ray , Hydrogen Bonding , Hydrophobic and Hydrophilic Interactions , Models, Molecular , Molecular Mimicry , Molecular Structure , Protein Binding , Pyridines/chemical synthesis , Quantitative Structure-Activity Relationship , Static Electricity , Triazoles/chemical synthesisABSTRACT
A series of N-hydroxycarbamates containing a histaminergic H(1) receptor antagonist pharmacophore was synthesized. In vitro assays determined the compounds had both histaminergic binding and 5-lipoxygenase inhibiting activities comparable to the corresponding N-hydroxyurea analog. Animal models demonstrated antihistaminergic and the 5-lipopxygenase inhibitory activity, with the N-hydroxyurea analog having a better overall profile.
Subject(s)
Hydroxamic Acids/chemical synthesis , Lipoxygenase Inhibitors , Animals , Blood , Guinea Pigs , Histamine H1 Antagonists/chemical synthesis , Histamine H1 Antagonists/chemistry , Humans , Hydroxamic Acids/pharmacology , Inhibitory Concentration 50 , Leukotriene B4/biosynthesis , Protein Binding , Structure-Activity RelationshipABSTRACT
The synthesis and in vitro p38 alpha activity of a novel series of benzimidazolone inhibitors is described. The p38 alpha SAR is consistent with a mode of binding wherein the benzimidazolone carbonyl serves as the H-bond acceptor to Met109 of p38 alpha in a manner analogous to the pyridine nitrogen of prototypical pyridylimidazole p38 inhibitors. Potent p38 alpha activity comparable to that of several previously reported p38 inhibitors is observed for this novel chemotype.
