Aryl O- and S-galactosides and lactosides as specific inhibitors of human galectins-1 and -3: role of electrostatic potential at O-3

Phase transfer catalyzed reaction was used for the high yielding synthesis of aryl 1-thio-beta-d-galacto- and lacto-pyranosides carrying a panel of substituents on the phenyl groups. Best galectin-1 inhibitors were simple p-nitrophenyl thiogalactoside 5a for the monosaccharide and o-nitrophenyl thiolactoside 6f or napthylsulfonyl lactoside 8c, both being 20 times better relative to natural ligands. Relative inhibitory properties as low as 2500 and 40 microM were observed, respectively. The electronic effects of the lactoside aglycons directly influenced the electrostatic potential at O-3, which was associated with the inhibitory potencies against galectin-1.     

Quaternary solution structures of galectins-1, -3, and -7

Galectins are a growing family of animal lectins with functions in growth regulation and cell adhesion that bind beta-Gal residues in oligosaccharides. Evidence indicates that some of the biological properties of galectins are due to their cross-linking activities with multivalent glycoconjugate receptors. Therefore determination of the quaternary solution structures of these proteins is important in understanding their structure-function properties. The present study reports analytical sedimentation velocity and equilibrium data for galectins-1, -3, and -7 in the absence and presence of bound LacNAc, the natural ligand epitope. Galectin-1 from bovine heart and recombinant human galectin-7 were found to be stable dimers by both methods. In contrast, recombinant murine galectin-3, as well as its proteolytical derived C-terminal domain, are predominantly monomeric. The presence of LacNAc at concentrations sufficient to fully saturate the proteins had no significant effect on either the weight average molecular weight determined by sedimentation equilibrium or the hydrodynamic properties determined from sedimentation velocity experiments. These results show that binding of a monovalent ligand does not affect oligomerization of these galectins.     

Synthesis and biological evaluation of 3-(azolylmethyl)-1H-indoles and 3-(alpha-azolylbenzyl)-1H-indoles as selective aromatase inhibitors

This present study identifies a number of azolyl-substituted indoles as potent inhibitors of aromatase. In the sub-series of 3-(azolylmethyl)-1H-indoles, four imidazole derivatives and their triazole analogues were tested. Imidazole derivatives 11 and 14 in which the benzyl moiety was substituted by 2-chloro and 4-cyano groups, respectively, were the most active, with IC50 values ranging between 0.054 and 0.050 microM. In the other sub-series, eight 3-(alpha-azolylbenzyl)-1H-indoles were prepared and tested. Compound 30, the N-ethyl imidazole derivative, proved to be an aromatase inhibitor, showing an IC50 value of 0.052 microM. All target compounds were further evaluated against 17alpha-hydroxylase/C17,20-lyase to determine their selectivity profile.     

Synthesis of potent and selective inhibitors of human plasma kallikrein

The synthesis and in vitro enzyme inhibition profile of a series of novel trifluoromethylketone (TFMK) inhibitors of human plasma kallikrein (PK) are described. We have developed an efficient method for the construction of peptide TFMKs that provides the final product devoid of compromised stereochemical integrity. Many of these compounds are potent inhibitors of PK and exhibit reduced inhibition of tissue kallikrein (TK) and plasmin (HP).     

Synthesis of potent and highly selective inhibitors of human tryptase

The serine protease tryptase has been implicated in allergic and inflammatory diseases and associated with asthma. The synthesis and SAR of a series of N1-activated-4-carboxy azetidinones are described, resulting in identification of BMS-363131 (2) as a potent inhibitor of human tryptase (IC(50)<1.7 nM) with high selectivity (>3000-fold) for tryptase versus related serine proteases including trypsin.     

1-Oxacephem-based human chymase inhibitors: discovery of stable inhibitors in human plasma

1-Oxacephem derivatives were evaluated as a novel series of chymase inhibitors. The structure-activity relationship studies of 1-oxacephems led to compounds 15, which exhibited 27 nM inhibition of human chymase and improvement of stability in human plasma (t 1/2 1.5 h).     

Synthesis and activity of novel 1- or 3-(3-amino-1-phenyl propyl)-1,3-dihydro-2H-benzimidazol-2-ones as selective norepinephrine reuptake inhibitors

A series of novel 1- or 3-(3-amino-1-phenyl propyl)-1,3-dihydro-2H-benzimidazol-2-ones as selective norepinephrine reuptake inhibitors was discovered. Several compounds such as 15 and 20 showed good hNET potency. Compounds 15 and 20 also displayed excellent selectivity at hNET that appeared superior to those of reboxetine and atomoxetine (4 and 5).     

Synthesis of potent and selective 2-azepanone inhibitors of human tryptase

The serine protease tryptase has been associated with a broad range of allergic and inflammatory diseases and, in particular, has been implicated as a critical mediator of asthma. The inhibition of tryptase therefore has the potential to be a valuable therapy for asthma. The synthesis, employing solution phase parallel methods, and SAR of a series of novel 2-azepanone tryptase inhibitors are presented. A member of this series, 8t, was identified as a potent inhibitor of human tryptase (IC(50)=38 nM) with selectivity >/=330-fold versus related serine proteases (trypsin, plasmin, uPA, tPA, APC, alpha-thrombin, and FXa) [corrected].     

Synthesis of 8-chloro-benzo[c]quinolizin-3-ones as potent and selective inhibitors of human steroid 5alpha-reductase 1

The synthesis of a series of differently substituted 8-chloro-benzo[c]quinolizin-3-ones, as potent and selective human steroid 5alpha-reductase type 1 inhibitors, has been accomplished by a four-step procedure based on the TiCl4-promoted tandem Mannich-Michael cyclization of 2-silyloxy-1,3-butadienes with N-t-Boc iminium ions from quinolin-2-ones. The presence on the benzo[c]quinolizinone nucleus of a methyl group and a double bond at positions 6 and 4-4a, respectively, as in compound 1d, gave rise to one of the most potent non-steroidal 5alphaR-1 inhibitors reported so far (IC50 = 14 nM).     

3-(1,2,3-Triazol-1-yl)-1-thio-galactosides as small, efficient, and hydrolytically stable inhibitors of galectin-3

Copper(I)-catalyzed addition of alkynes to methyl 3-azido-3-deoxy-1-thio-beta-D-galactopyranoside afforded stable and structurally simple 3-deoxy-3-(1H-1,2,3-triazol-1-yl)-1-thio-galactosides carrying a panel of substituents at the triazole C4 in high yields. The 3-(1H-[1,2,3]-triazol-1-yl)-1-thio-galactoside collection synthesized contained inhibitors of the tumor- and inflammation-related galectin-3 with Kd values as low as 107 microM, which is as potent as the natural disaccharide inhibitors lactose and N-acetyllactosamine.     

Synthesis and activity of 1-(3-amino-1-phenylpropyl)indolin-2-ones: a new class of selective norepinephrine reuptake inhibitors

Norepinephrine and serotonin play an important role in a wide variety of biological processes and are implicated in a number of neurological disorders. A novel class of 1-(3-amino-1-phenylpropyl)indolin-2-ones was designed and synthesized that displays potent norepinephrine reuptake inhibition while maintaining high selectivity (>100-fold) against the human serotonin and dopamine transporters.     

Synthesis of potent and highly selective nonguanidine azetidinone inhibitors of human tryptase

Azetidinones such as BMS-363131 (2) and BMS-363130 (3), which contain a guanidine group in the C-3 side chain were previously shown to be very potent inhibitors of human tryptase with high selectivity versus other serine proteases, including trypsin. In this letter, we describe the discovery of a number of potent azetidinone tryptase inhibitors in which the guanidine moiety at the ring C-3 position is replaced with primary or secondary amine or aminopyridine functionality. In particular, BMS-354326 (4) is a highly potent tryptase inhibitor (IC(50)=1.8 nM), which has excellent selectivity against trypsin and most other related serine proteases.     

Synthesis of non-prenyl analogues of baccharin as selective and potent inhibitors for aldo-keto reductase 1C3

Inhibitors of a human member (AKR1C3) of the aldo-keto reductase superfamily are regarded as promising therapeutics for the treatment of prostatic and breast cancers. Baccharin [3-prenyl-4-(dihydrocinnamoyloxy)cinnamic acid], a component of propolis, was shown to be both potent (K_i 56 nM) and highly isoform-selective inhibitor of AKR1C3. In this study, a series of derivatives of baccharin were synthesized by replacing the 3-prenyl moiety with aryl and alkyl ether moieties, and their inhibitory activities for the enzyme were evaluated. Among them, two benzyl ether derivatives, 6m and 6n, showed an equivalent inhibitory potency to baccharin. The molecular docking of 6m in AKR1C3 has allowed the design and synthesis of (E)-3-{3-[(3-hydroxybenzyl)oxy]-4-[(3-phenylpropanoyl)oxy]phenyl}acrylic acid (14) with improved potency (K_i 6.4 nM) and selectivity comparable to baccharin. Additionally, 14 significantly decreased the cellular metabolism of androsterone and cytotoxic 4-oxo-2-nonenal by AKR1C3 at much lower concentrations than baccharin.     

Synthesis of selective SRPK-1 inhibitors: novel tricyclic quinoxaline derivatives

SR protein-specific kinase-1 (SRPK-1) has been identified as a validated target for hepatitis B virus (HBV). A series of novel tricyclic quinoxaline derivatives was designed and synthesised as potential kinase inhibitory antiviral agents and was found to be active and selective for SRPK-1 kinase. Most of these novel compounds have drug-like properties according to experimentally determined LogP and LogS values.     

Synthesis and biological evaluation of 5-[(aryl)(1H-imidazol-1-yl)methyl]-1H-indoles: potent and selective aromatase inhibitors

The synthesis and the aromatase (CYP19) inhibitory activity of 5-[(aryl)(imidazol-1-yl)methyl]-1H-indoles were reported. Among the tested racemate compounds, 5-[(4-chlorophenyl)(1H-imidazol-1-yl)methyl]-1H-indole 8b emerged as a potent CYP19 inhibitor (IC(50)=15.3 nM). Chiral chromatography allowed isolation of the (+) enantiomer 8b2, which was about twice as active as the racemate (IC(50)=9 nM).     

Synthesis and activity of quinolinyl-methylene-thiazolinones as potent and selective cyclin-dependent kinase 1 inhibitors

A novel series of quinolinyl-methylene-thiazolinones has been identified as potent and selective cyclin-dependent kinase 1 (CDK1) inhibitors. Their synthesis and structure activity relationships (SAR) are described. Representative compounds from this class reversibly inhibit CDK1 activity in vitro, and block cell cycle progression in human tumor cell lines, suggesting a potential use as antitumor agents.     

Synthesis of galactose-mimicking 1H-(1,2,3-triazol-1-yl)-mannosides as selective galectin-3 and 9N inhibitors

1H-[1,2,3]-Triazol-1-yl mannosides have been synthesized as inhibitors for the beta-galactoside-binding family of galectin proteins. Easier synthetic access to C1 in mannose, as compared to C3 in galactose, for attachment of affinity-enhancing triazoles rendered a synthetic advantage. The best mannose-derived inhibitor for galectin-9N, 4-benzylaminocarbonyl-1H-[1,2,3]-triazol-1-yl beta-D-mannopyranoside, had a Kd value of 540 microM, which compares favorably with its galactoside counterpart (Kd=670 microM) and with LacNAc (Kd=500 microM).     

Synthesis of 1H-pyridin-2-one derivatives as potent and selective farnesyltransferase inhibitors

Two novel series of potent and selective FTase inhibitors have been synthesized using structure-based design. Medicinal chemistry efforts led to the discovery of compound 4e with potent cellular activity and good oral bioavailability in dog. A synthetic route toward novel heterocycles 1,5-dimethyl-6-oxo-4-aryl-1,6-dihydro-pyridine-2-carbonitrile was established. The structure of compound 5c was confirmed by X-ray crystallography.     

Synthesis and evaluation of 6-methyl-3-phenylcoumarins as potent and selective MAO-B inhibitors

A series of 6-methyl-3-phenylcoumarins 3-6 were synthesized and evaluated as monoamine oxidase A and B (MAO-A and MAO-B) inhibitors. A comparative study between the three possible mono methoxy 3-phenyl derivatives and the p-hydroxy analogue is reported. The synthesis of these new resveratrol-coumarin hybrids was carried out by a Perkin reaction between the 5-methylsalicylaldehyde and the corresponding phenylacetic acids. The p-methoxy substituted compound 3 was hydrolyzed to 6 by a traditional reaction with hydriodic acid. The prepared compounds show high selectivity to the MAO-B isoenzyme, some of them with IC₅₀ values in the low nanomolar range. Compound 4, with the methoxy group in meta position, is the most active of this series, with an IC₅₀ against MAO-B of 0.80 nM, and is several times more potent and MAO-B selective than the R-(?)-deprenyl (reference compound).     

Synthesis and pharmacological evaluation of 3-aryl-3-azolylpropan-1-amines as selective triple serotonin/norepinephrine/dopamine reuptake inhibitors

A series of 3-aryl-3-azolylpropan-1-amines was prepared and screened for its capability of inhibiting monoamine reuptake. Analogs with nanomolar potency, good human in vitro microsomal stability, and low drug–drug interaction potential were described. In vivo models were used to evaluate the compound 19r for antidepressive, anxiolytic, and analgesic activity.