ABSTRACT
The IC50 of a beta-secretase (BACE-1) lead compound was improved â¼200-fold from 11 µM to 55 nM through the addition of a single methyl group. Computational chemistry, small molecule NMR, and protein crystallography capabilities were used to compare the solution conformation of the ligand under varying pH conditions to its conformation when bound in the active site. Chemical modification then explored available binding pockets adjacent to the ligand. A strategically placed methyl group not only maintained the required pKa of the piperidine nitrogen and filled a small hydrophobic pocket, but more importantly, stabilized the conformation best suited for optimized binding to the receptor.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Hydantoins/chemistry , Hydantoins/pharmacology , Amyloid Precursor Protein Secretases/metabolism , Aspartic Acid Endopeptidases/metabolism , Crystallography, X-Ray , Dose-Response Relationship, Drug , Humans , Hydantoins/chemical synthesis , Methylation , Models, Molecular , Molecular Structure , Structure-Activity RelationshipABSTRACT
This communication reports a new synthetic route of pyridopyrimidines to facilitate their structural optimization in a library fashion and describes the development of pyridopyrimidines that have excellent enzymatic and cell potency against Akt1 and Akt2. This series also shows a high level of selectivity over other closely related kinases and significantly improved caspase-3 activity with the more optimized compounds.
Subject(s)
Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Amines/chemical synthesis , Amines/chemistry , Amines/pharmacology , Caspase 3/metabolism , Cell Line, Tumor , Dose-Response Relationship, Drug , Humans , Inhibitory Concentration 50 , Piperidines/chemical synthesis , Piperidines/chemistry , Piperidines/pharmacology , Protein Kinase Inhibitors/chemistry , Pyrimidines/chemistry , Structure-Activity Relationship , TNF-Related Apoptosis-Inducing Ligand/pharmacologyABSTRACT
The kinesin spindle protein (KSP, also known as Eg5) is essential for the proper separation of spindle poles during mitosis, and inhibition results in mitotic arrest and the formation of characteristic monoaster spindles. Several distinct classes of KSP inhibitors have been described previously in the public and patent literature. However, most appear to share a common induced-fit allosteric binding site, suggesting a common mechanism of inhibition. In a high-throughput screen for inhibitors of KSP, a novel class of thiazole-containing inhibitors was identified. Unlike the previously described allosteric KSP inhibitors, the thiazoles described here show ATP competitive kinetic behavior, consistent with binding within the nucleotide binding pocket. Although they bind to a pocket that is highly conserved across kinesins, these molecules exhibit significant selectivity for KSP over other kinesins and other ATP-utilizing enzymes. Several of these compounds are active in cells and produce a phenotype similar to that observed with previously published allosteric inhibitors of KSP.
Subject(s)
Adenosine Triphosphate/metabolism , Biochemistry/methods , Kinesins/antagonists & inhibitors , Kinesins/chemistry , Mitosis , Adenosine Triphosphate/chemistry , Allosteric Site , Binding, Competitive , Drug Design , Humans , Kinesins/metabolism , Models, Biological , Models, Chemical , Nucleotides/chemistry , Phenotype , Protein Binding , Thiazoles/pharmacologyABSTRACT
Observations from two structurally related series of KSP inhibitors led to the proposal and discovery of dihydropyrazolobenzoxazines that possess ideal properties for cancer drug development. The synthesis and characterization of this class of inhibitors along with relevant pharmacokinetic and in vivo data are presented. The synthesis is highlighted by a key [3+2] cycloaddition to form the pyrazolobenzoxazine core followed by diastereospecific installation of a quaternary center.
Subject(s)
Benzoxazines/chemistry , Benzoxazines/pharmacology , Drug Design , Kinesins/antagonists & inhibitors , Kinesins/metabolism , Mitosis/drug effects , Pyrazoles/chemistry , Animals , Benzoxazines/chemical synthesis , Benzoxazines/pharmacokinetics , Cell Line , Dogs , Humans , Hydrogen/chemistry , Molecular Structure , Structure-Activity RelationshipABSTRACT
A series of N,N-dialkyl-4-(9-aryltropanylidenemethyl)benzamides was prepared. The lead compounds, 15a and 15c, exhibited extremely high affinity for the delta opioid receptor with excellent selectivity versus the micro opioid receptor. They were full agonists at the delta opioid receptor, as assessed by stimulation of GTPgammaS binding, and displayed antinociceptive activity.
