Sulfonamido-derivatives of unsubstituted carbazoles as BACE1 inhibitors.

A novel series of variously substituted N-[3-(9H-carbazol-9-yl)-2-hydroxypropyl]-arylsulfonamides has been synthesized and assayed for ß-Secretase (BACE1) inhibitory activity. BACE1 is a widely recognized drug target for the prevention and treatment of Alzheimer's Disease (AD). The introduction of benzyl substituents on the nitrogen atom of the arylsulfonamide moiety has so far led to the best results, with three derivatives showing IC50 values ranging from 1.6 to 1.9 µM. Therefore, a significant improvement over the previously reported series of N-carboxamides (displaying IC50's ≥ 2.5 µM) has been achieved, thus suggesting an active role of the sulfonamido-portion in the inhibition process. Preliminary molecular modeling studies have been carried out to rationalize the observed structure-activity relationships.

Carbazole-containing arylcarboxamides as BACE1 inhibitors.

ß-Secretase (BACE1) is widely recognized as a prime drug target for the treatment of Alzheimer's disease (AD). In this Letter, we report the synthesis and the BACE1 inhibitory activity of novel, variously substituted N-[3-(9H-carbazol-9-yl)-2-hydroxypropyl]-arylcarboxamides. The best results have been obtained with the introduction of a 4-OMe substituent (IC(50)=3.8 µM) or a 3,4-dichloro substituent (IC(50)=2.5 µM) in the amidic aromatic ring. The blood-brain barrier penetration predictions resulted to be promising for this type of compounds. To better understand the structure-activity relationships (SAR) of the new derivatives, a docking study procedure has been applied exploiting different conformational and ionic states of BACE1.

BACE1 inhibitory activities of enantiomerically pure, variously substituted N-(3-(4-benzhydrylpiperazin-1-yl)-2-hydroxypropyl) arylsulfonamides.

ß-Secretase (BACE1) has been widely recognized as one of the possible therapeutic targets for the treatment of Alzheimer's disease. In this paper, we report the synthesis and the BACE1 inhibitory activity of new, variously substituted N-(3-(4-benzhydrylpiperazin-1-yl)-2-hydroxypropyl) arylsulfonamides. Each enantiomeric form was separately evaluated in BACE1 inhibition assays and IC(50) values were obtained in the low micromolar range. According to our biological results and docking studies, it can be asserted that the stereochemistry around the OH group in the central hydroxyethylamino linker does not significantly influence the BACE1 inhibitory activity of this type of molecules.

Variously substituted (phosphonoacetamido)oxy analogues of geranylgeranyl diphosphate (GGdP) as GGdP-transferase (GGTase) inhibitors and antiproliferative agents.

Aberrant signalling through the pathways of small GTP-binding proteins, belonging to the Ras superfamily (Ras, Rho, Rac, Cdc42 etc.), occurs in several types of cancer, where mutated Ras accumulates in its GTP-bound active form and causes uncontrolled cell proliferation. For these reasons, molecules able to target the Ras pathway in any of its stages are potentially useful in anti-cancer therapies. Inhibition of farnesyl-protein transferase (FTase), the enzyme that post-translationally activates Ras, has been pursued for the obvious role of the Ras oncoprotein in human malignancies. It was later found that some mutated forms of Ras (K- and N-Ras) can also be geranylgeranylated by geranylgeranyl-protein transferase (GGTase) when FTase is blocked, circumventing the antiproliferative effects of FTase inhibitors. Therefore, a new task has been the search for new GGTase inhibitors, which can also interfere on cell proliferation by blocking the isoprenylation of other Ras superfamily proteins (i.e. Rho, Rac, Cdc42) involved in the regulation of cell cycle progression. We have recently described a series of phosphonoacetamido- and phosphonoacetamidoxy-stable analogues of geranylgeranyl-diphosphate (GGdP) possessing good GGTase inhibitory properties and, some of them, also remarkable GGTase/FTase selectivity levels. We have now extended this series to a larger number of variously substituted phosphonoacetamidoxy-analogues of GGdP in order to establish the effect on GGTase inhibitory activity and selectivity due to the presence of different substituents in the polar portion of these GGdP mimics. We have also measured the cytotoxicity of these compounds on tumour cell lines with the aim of evaluating their potential anti-proliferative effects.

Stable propylphosphonic acid analogues of geranylgeranyl diphosphate possessing inhibitory activity on geranylgeranyl protein transferase.

Stable analogues of geranylgeranyl diphosphate, possessing 3-(phosphono)propionamido moieties in the place of the metabolically unstable diphosphate portion, were prepared and submitted to prenyltransferase (GGTase and FTase) inhibition assays. In one case, an excellent GGTase inhibitory activity was obtained (IC(50) = 39 nM), accompanied by a certain degree of GGTase vs. FTase selectivity.