Naphthamidine urokinase plasminogen activator inhibitors with improved pharmacokinetic properties

A series of non-amide-linked 6-substituted-2-naphthamidine urokinase plasminogen activator (uPA) inhibitors are described. These compounds possess excellent binding activities and selectivities with significantly improved pharmacokinetic profiles versus previously described amide-linked inhibitors.     

Towards the control of intracellular protein turnover: mitochondrial Lon protease inhibitors versus proteasome inhibitors

Cellular protein homeostasis results from the combination of protein biogenesis processes and protein quality control mechanisms, which contribute to the functional state of cells under normal and stress conditions. Proteolysis constitutes the final step by which short-lived, misfolded and damaged intracellular proteins are eliminated. Protein turnover and oxidatively modified protein degradation are mainly achieved by the proteasome in the cytosol and nucleus of eukaryotic cells while several ATP-dependent proteases including the matrix protease Lon take part in the mitochondrial protein degradation. Moreover, Lon protease seems to play a major role in the elimination of oxidatively modified proteins in the mitochondrial matrix. Specific inhibitors are commonly used to assess cellular functions of proteolytic systems as well as to identify their protein substrates. Here, we present and discuss known proteasome and Lon protease inhibitors. To date, very few inhibitors of Lon have been described and no specific inhibitors of this protease are available. The current knowledge on both catalytic mechanisms and inhibitors of these two proteases is first described and attempts to define specific non-peptidic inhibitors of the human Lon protease are presented.     

Discovery and biochemical characterization of selective ATP competitive inhibitors of the human mitotic kinesin KSP

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.     

Development of pyrimidine-based inhibitors of Janus tyrosine kinase 3

A new class of pyrimidine-based Janus tyrosine kinase 3 (JAK3) inhibitors are described. Many of these inhibitors showed low nanomolar activity against JAK3.     

A new series of potent benzodiazepine gamma-secretase inhibitors

A new series of benzodiazepine-containing gamma-secretase inhibitors with potential use in the treatment of Alzheimer's disease is disclosed. Structure-activity relationships of the pendant hydrocinnamate side-chain which led to the preparation of highly potent inhibitors are described.     

Inhibitors of Plant Copper Amineoxidases

Abstract

In this review, inhibitors of plant copper amine oxidases from Lens esculenta seedlings, Pisum sativum seedlings, and Euphorbia characias latex are described. Reversible competitive inhibitors and non-competitive inhibitors, irreversible active-site directed inhibitors and mechanism-based inactivators are reviewed in regard to their mechanisms of action.     

Development of new pyrrolopyrimidine-based inhibitors of Janus kinase 3 (JAK3)

A new class of bicyclic pyrrolopyrimidine-based Janus kinase 3 (JAK-3) inhibitors are described. Many of these inhibitors showed low nanomolar activity against JAK-3.     

Kinesin spindle protein (KSP) inhibitors. Part 8: Design and synthesis of 1,4-diaryl-4,5-dihydropyrazoles as potent inhibitors of the mitotic kinesin KSP

Inspired by previous efforts in the pyrazolobenzoxazine class of KSP inhibitors, the design and synthesis of 1,4-diaryl-4,5-dihydropyrazole inhibitors of KSP are described. Crystallographic evidence of binding mode and in vivo potency data is also highlighted.     

Isolation and characterization of three protein proteinase isoinhibitors from the granular fraction of horse neutrophilic granulocytes

Three cathodically migrating protein protease isoinhibitors were isolated from the granule-rich fraction of equine neutrophilic granulocytes by means of FPLC chromatography, in addition to two previously described anodically migrating inhibitors. The three isoinhibitors had an identical enzyme specificity which was equal to the two previously described isoinhibitors; they inhibited exclusively proteinase K and subtilisin. The inhibitors retained their activity between pH 1 and 12. They also were heat stable at 100 degrees C for 20 min. Neither the biological function of isoinhibitors nor the fundamental role of granular protease inhibitors of such narrow and peculiar enzyme specificity are known.     

Wheat protein inhibitors of α-amylase

The location in the seed, molecular properties and biological role of protein α-amylase inhibitors from wheat are discussed. Inhibition specificity of albumin inhibitors and structural features essential for interaction with inhibited amylases are also examined. The possible significance of these naturally occurring inhibitors in relation to their presence in foods in active form is described. Finally, genetic aspects of the albumin inhibitor production and the possibility of improving nutritional value and insect re     

Synthesis and biological activity of peptidyl aldehyde urokinase inhibitors

Solid- and solution-phase synthesis of peptidomimetic inhibitors of urokinase-type plasminogen activator based on the sequence dSerAlaArg-al are described. The biological activities of these unique inhibitors are reported herein. Carbonate prodrugs were prepared and tested as potential drug delivery systems.     

Discovery of 2-arylquinazoline derivatives as a new class of ASK1 inhibitors

The development of a new series of apoptosis signal-regulating kinase 1 (ASK1) inhibitors is described. Starting from purine, pyrimidine and quinazoline scaffolds identified by high throughput screening, we used tools of structure-based drug design to develop a series of potent kinase inhibitors, including 2-arylquinazoline derivatives 12 and 23, with submicromolar inhibitory activities against ASK1. Kinetic analysis demonstrated that the 2-arylquinazoline scaffold ASK1 inhibitors described herein are ATP competitive.     

Discovery and SAR studies of novel GlyT1 inhibitors

Inhibition of the glycine transporter GlyT1 is a potential strategy for the treatment of schizophrenia. A novel series of GlyT1 inhibitors and their structure-activity relationships (SAR) are described. Members of this series are highly potent and selective transport inhibitors which are shown to elevate glycine levels in cerebrospinal fluid.     

Synthesis and optimization of arylsulfonylpiperazines as a novel class of inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1)

The synthesis and SAR of a series of arylsulfonylpiperazine inhibitors of 11β-HSD1 are described. Optimization rapidly led to potent, selective, and orally bioavailable inhibitors demonstrating efficacy in a cynomolgus monkey ex vivo enzyme inhibition model.     

HIV-1 protease inhibitors containing statine: inhibitory potency and antiviral activity.

Several series of chemically different inhibitors of the HIV-1 aspartyl protease have been described. Nevertheless despite the high in vitro potency showed, in most cases these inhibitors are unable to inhibit viral replication in infected cells. Penetration of the inhibitors across the cell membrane might account for their low antiviral activity. The relationship between inhibitory potency, antiviral activity and chemical structures of a series of oligopeptides containing statine or statine derivatives are presented here.     

Design and synthesis of multisubstrate analog inhibitors of one-carbon transfer reactions

The design and synthesis of multisubstrate analog enzyme inhibitors offer new opportunities in the creation of potent, highly specific drug molecules. Selected examples of inhibitors of 1-carbon transfer serve to illustrate the potential of this approach. Inhibitors of indole-N-methyltransferase, L-aspartyl transcarbamoylase, and thymidylate synthase are illustrative of many compounds that have demonstrated considerable specificity and potency. Several of these inhibitors and the rationale for their syntheses are described.     

Dibasic inhibitors of human mast cell tryptase. Part 1: synthesis and optimization of a novel class of inhibitors

The synthesis and optimization of a novel class of reversible and active-site directed dibasic inhibitors of human mast cell tryptase are described. The compounds were shown to be both remarkably potent and selective for tryptase with Ki values for optimized inhibitors in the picomolar range.     

Synthesis and characterization of azole isoflavone inhibitors of aromatase

The synthesis and biological evaluation of a series of 2-azole and 2-thioazole isoflavones as potential aromatase inhibitors are described. Differences in inhibitory activity of triazole and imidazole inhibitors are rationalized with density functional theory to expose a key difference in the electronic structure of these molecules. In addition, difference binding spectra of inhibitors to immunoaffinity-purified aromatase produces classical Type II spectra consistent with coordination of the nitrogen lone pair electrons to the aromatase P450 heme.     

4-Phenyl-7-azaindoles as potent and selective IKK2 inhibitors

The synthesis and SAR of a novel series of IKK2 inhibitors are described. Modification around the hinge binding region of the 7-azaindole led to a series of potent and selective inhibitors with good cellular activity.     

Synthesis and optimization of novel 4,4-disubstituted cyclohexylbenzamide derivatives as potent 11β-HSD1 inhibitors

The synthesis and SAR of a series of 4,4-disubstituted cyclohexylbenzamide inhibitors of 11β-HSD1 are described. Optimization rapidly led to potent, highly selective, and orally bioavailable inhibitors demonstrating efficacy in both rat and non-human primate ex vivo pharmacodynamic models.