3,4-Fused cyclohexyl sulfones as gamma-secretase inhibitors

The 3,4-fused sulfamides, sulfonamides and sulfone have been identified as highly potent gamma-secretase inhibitors. Evaluation of the SAR of substitution within these series has allowed the identification of a range of compounds which significantly reduce brain A beta in transgenic mouse models and thus have potential as possible treatments for Alzheimer's disease.     

Peptidyl allyl sulfones: a new class of inhibitors for clan CA cysteine proteases

A new series of peptidyl allyl sulfone inhibitors was discovered while trying to synthesize epoxy sulfone inhibitors from vinyl sulfones using basic oxidizing conditions. The various dipeptidyl allyl sulfones were evaluated with calpain I, papain, cathepsins B and L, cruzain and rhodesain and found to be potent inhibitors. In comparison to the previously developed class of vinyl sulfone inhibitors, the novel dipeptidyl allyl sulfones were more potent inhibitors than the corresponding dipeptidyl vinyl sulfones. It was observed that the stereochemistry of the vinyl sulfone precursor played a role in the potency of the dipeptidyl allyl sulfone inhibitor.     

4-substituted cyclohexyl sulfones as potent, orally active gamma-secretase inhibitors

The protease gamma-secretase plays a pivotal role in the synthesis of pathogenic amyloid-beta in Alzheimer's disease (AD). Here, we report a further extension to a series of cyclohexyl sulfone-based gamma-secretase inhibitors which has allowed the preparation of highly potent compounds which also demonstrate robust Abeta(40) lowering in vivo (e.g., compound 32, MED 1mg/kg p.o. in APP-YAC mice).     

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.     

Tetraketones: a new class of tyrosinase inhibitors

Twenty-eight tetraketones (1-28) with variable substituents at C-7 were synthesized and evaluated as tyrosinase inhibitors. Remarkably compounds 25 (IC(50)=2.06 microM), 11 (IC(50)=2.09 microM), 15 (IC(50)=2.61 microM), and 27 (IC(50)=3.19 microM) were found to be the most active compounds of the series, even better than both standards kojic acid (IC(50)=16.67 microM) and L-mimosine (IC(50)=3.68 microM). This study may lead to the discovery of therapeutically potent agents against clinically very important dermatological disorders including hyperpigmentation as well as skin melanoma.     

N-Benzylbenzamides: a new class of potent tyrosinase inhibitors

A series of potent inhibitors of tyrosinase and their structure-activity relationships are described. N-Benzylbenzamide derivatives (1-21) with hydroxyl(s) were synthesized and tested for their tyrosinase inhibitory activity. With this series, compound 15 provided a potent tyrosinase inhibition: it effectively inhibited the oxidation of l-DOPA catalyzed by mushroom tyrosinase with an IC(50) of 2.2microM.     

Dipeptide glycols: a new class of renin inhibitors

The discovery of a new class of novel renin inhibitors consisting of protected dipeptide amides derived from aminoglycols (Formula I) prompted a study of structure-activity in vitro and efficacy in vivo. Thus, Boc-L-Phe-N-[(1S,2R)-1-benzyl-(2,3-dihydroxy)propyl]-L-leucinamide (1) and the corresponding histidinamide (2) inhibit human renin in vitro (IC50: 8.7 X 10-6 M and 2.6 X 10-6 M, respectively). Compound 1 has a slight inhibitory effect on pepsin and compound 2 does not inhibit pepsin at all (at 10-4M); these compounds are inactive against rat renin. Compound 1 is efficacious in lowering plasma renin activity in the Rhesus monkey (i.v.). Results indicate that this new class of low molecular weight inhibitors is specific for human renin and thus constitutes a new source of drug candidates.     

N-nitrosoanilines: a new class of caspase-3 inhibitors

Caspases are a family of cysteine proteases activated during apoptosis. In cultured human endothelial cells, physiological levels of NO prevent apoptosis and interfere with the activation of the caspase cascade. Previous studies have demonstrated that NO inhibits the activity of caspase-3 by S-nitrosylation of the enzyme. In this study, the inhibitory effect of a new class of NO donors. N-nitrosoaniline derivatives, were examined against caspase-3. Initially eight small molecule inhibitors bearing N-nitroso moieties were assayed. It was found that the presence of an electron-donating group on the phenyl ring led to better inhibitory potency, a trend consistent with the results from the previous papain studies. Based on the analysis of the enzyme and substrates' structures, two peptidyl N-nitrosoaniline inhibitors [Ac-DVAD-NNO (1) and Ac-DV-AMO (2)] were designed and synthesized. Both compounds exhibited enhanced inhibitory potency against caspase-3.     

Azapeptides: a new class of angiotensin-converting enzyme inhibitors

A class of potent inhibitors of angiotensin-converting enzyme (dipeptidyl carboxypeptidase, E.C. 3.4.15.1) is reported, in which an alpha-aza substitution into the substituted N-carboxymethyl dipeptide structure of enalapril is made. The inhibitors 2 exhibit striking alterations in their conformational and acid-base properties due to the aza substitution, as is clear from pKa data and the x-ray crystal structure of a model azapeptide. In spite of this, they bind tightly to the enzyme, with inhibitor potency comparable to that of captopril.     

Cyclic sulfamide gamma-secretase inhibitors

A novel series of N-alkyl-substituted cyclic sulfamides were developed from a screening hit. Chemistries were developed which allowed surveys of N-alkyl groups and amines resulting in the identification of N-trifluoroethyl-substituted cyclic sulfamides with good in vitro and in vivo gamma-secretase activity. One compound with subnanomolar activity elicited a reduction in brain Abeta40 after oral dosing in APP-YAC mice.     

Periodinates: a new class of protein tyrosine phosphatase inhibitors

A series of periodinates has been synthesized and tested as protein tyrosine phosphatase substrates. Their potency is comparable to or higher than that of vanadates but much lower than that of peroxovanadates.     

Benzodipyrazoles: a new class of potent CDK2 inhibitors

The synthesis and the preliminary expansion of this new class of CDK2 inhibitors are presented. The synthesis was accomplished using a solution-phase protocol amenable to rapid parallel expansion and suitable to be scaled-up in view of possible lead development. Following a medicinal chemistry program aimed at improving cell permeability and selectivity, a series of compounds with nanomolar activity in the biochemical assay and able to efficiently inhibit tumor cell proliferation has been obtained.     

Tetrahydroquinoline sulfonamides as gamma-secretase inhibitors

The development of a novel series of tetrahydroquinoline-derived gamma-secretase inhibitors for the potential treatment of Alzheimer's disease is described.     

Thiazole-diamides as potent gamma-secretase inhibitors

The thiazole-diamide series (1) has been identified as highly potent gamma-secretase inhibitors. Several representative compounds showed IC(50) values of <0.3 nM. The synthesis and SAR, as well as a radiolabeled synthesis of [(3)H]-2a, are described.     

Hydroxytriamides as potent gamma-secretase inhibitors

Using a cell-based assay, we have identified optimal residues and key recognition elements necessary for inhibition of gamma-secretase. An (S)-hydroxy group or 3,5-difluorophenylacetyl group at the amino terminus and N-methyltertiary amide moiety at the carboxy terminus provided potent gamma-secretase inhibitors with an IC(50) <10 nM.     

QSAR studies--potent benzodiazepine gamma-secretase inhibitors

A series of benzodiazepine compounds, which act as gamma-secretrase inhibitors were subjected to QSAR studies. A correlation between the physicochemical properties QlogP, SMR and the inhibitory activity was obtained and a model equation was generated to predict the best possible pharmacophore for treating Alzheimer's disease. The inhibitory activity of the compound depends on the lipophilicity positively and is sensitive to small changes in its SMR. The compound with a high lipophilicity (around 9.31) and low SMR gives a potent activity.     

Discovery of a novel series of Notch-sparing gamma-secretase inhibitors

Using a cell-based assay, we have identified a new series of Notch-sparing γ-secretase inhibitors from HTS screening leads 2a and 2e. Lead optimization studies led to the discovery of analog 8e with improved γ-secretase inhibitory potency and Notch-sparing selectivity.     

Amino-caprolactam derivatives as gamma-secretase inhibitors

A series of amino-caprolactam sulfonamides were developed from a screening hit. Compounds with good in vitro and in vivo gamma-secretase activity are reported.     

Carbamate-appended N-alkylsulfonamides as inhibitors of gamma-secretase

The synthesis and gamma-secretase inhibition data for a series of carbamate-appended N-alkylsulfonamides are described. Carbamate 54 was found to significantly reduce brain Abeta in transgenic mice. 54 was also found to possess markedly improved brain levels in transgenic mice compared to previously disclosed 1 and 2.