Identification of a novel arylpiperazine scaffold for fatty acid amide hydrolase inhibition with improved drug disposition properties.

We herein describe the systematic approach used to develop new analogues of compound 2, recently identified as a potent and selective fatty acid amide hydrolase (FAAH) inhibitor. Aiming at identifying new scaffolds endowed with improved drug disposition properties with respect to the phenylpyrrole-based lead, we subjected it to two different structural modification strategies. This process allowed the identification of derivatives 4b and 5c as potent, reversible and non-competitive FAAH inhibitors.

Direct B-alkyl Suzuki-Miyaura cross-coupling of 2-halopurines. Practical synthesis of ST1535, a potent adenosine A2A receptor antagonist.

The scope and limitations of using palladium-catalyzed cross-coupling reactions of diverse butyl metal species with two different 2-halopurines were evaluated. While tributylboranes reacted readily and regioselectively with both 2-chloro-6-dibenzylaminopurines and 2-iodo-6-chloropurines, all the other alkyl metal species were much less reactive and gave very poor yield and/or selectivity of the desired product. This protocol was applied to the synthesis of an important adenosine A(2A) receptor antagonist, ST1535.

Liposomes from a new chiral cationic lipid based on iridoidic template.

A new cationic polyhydroxylated lipid, characterized by a chiral template, was synthesized. It comes from an iridoid glucoside, as polyhydroxylated moiety. This lipid affords liposomes using cholesterol-like co-lipid. The liposomes had a spheroidal shape with a small size distribution.

Polar constituents, protection against reactive oxygen species, and nutritional value of Chinese artichoke (Stachys affinis Bunge).

In the present work, we studied the chemical composition of Chinese artichoke (S. affinis tubers) by analyzing its polar constituents and its macro- and micro- nutrients. A total of nine compounds were isolated from the tuber ethanolic extract and structurally elucidated by Nuclear Magnetic Resonance (NMR) spectroscopy and mass spectrometry (MS). The marker compounds identified were oligosaccharide stachyose and the organic acid, succinic acid, as well as phenylethanoid and iridoid glycosides. The macronutrient profile was dominated by carbohydrates (36.9% dw), whereas potassium (2.36%) was the most abundant micro-nutrient. The tuber ethanolic extract was able to efficiently protect human cells (Caco-2, SHSY-5Y and K562) against t-BHP-induced oxidative damage.

Towards the development of 5-HT7 ligands combining serotonin-like and arylpiperazine moieties.

Many known 5-HT7 ligands contain either a serotonin-like or an arylpiperazine structure that, in published SAR studies, are generally supposed to bind the same receptor pocket. Conversely, we explored the hypothesis that two such moieties can co-exist in the same ligand, binding to different pockets. We thus designed and synthesized a set of compounds including both a 5-hydroxyindol-3-ylethyl and a 1-arylpiperazine moieties connected by a short linker. The compounds were tested for their affinity for human 5-HT7 serotonin receptor. We further prepared a novel series of 5-HT7 ligands, where the 5-hydroxyindol-3-ylethyl moiety was bioisosterically replaced by a 3-hydroxyanilinoalkyl one. Among the newly synthesized compounds, potent ligands at the 5-HT7 receptor, behaving as antagonists in functional tests, were identified, even if they showed limited subtype selectivity. Docking studies within a model of the 5-HT7 receptor showed that the binding site can actually accommodate both moieties, with the serotonin-like one in the putative orthosteric site and the arylpiperazine one occupying an accessory pocket. The present results demonstrate that it is possible to devise and develop new 5-HT7 ligands merging two privileged structures in the same molecule.

Design, synthesis, and structure-activity relationship of N-arylnaphthylamine derivatives as amyloid aggregation inhibitors.

Dyes like CR are able to inhibit the aggregation of Aß fibrils. Thus, a screening of a series of dyes including ABBB (1) was performed. Its main component 2 tested in an in vitro assay (i.e., ThT assay) showed good potency at inhibiting fibrils association. Congeners 4-9 have been designed and synthesized as inhibitors of Aß aggregation. A number of these newly synthesized compounds have been found to be active in the ThT assay with IC(50) of 1-57.4 µM. The most potent compound of this series, 4k, showed micromolar activity in this test. Another potent derivative 4q (IC(50) = 5.6 µM) rapidly crossed the blood-brain barrier, achieving whole brain concentrations higher than in plasma. So 4q could be developed to find novel potent antiaggregating ßA agents useful in Alzheimer disease as well as other neurological diseases characterized by deposits of amyloid aggregates.