Anilinotriazoles as potent gamma secretase modulators.

The design and synthesis of a novel series of potent gamma secretase modulators is described. Exploration of various spacer groups between the triazole ring and the aromatic appendix in 2 has led to anilinotriazole 28, which combined high in vitro and in vivo potency with an acceptable drug-like profile.

Design and synthesis of bicyclic heterocycles as potent γ-secretase modulators.

The evolution of amide 3 into conformationally restricted bicyclic triazolo-piperidine 14-S as a γ-secretase modulator is described. This is a potential disease modifying anti-Alzheimer's drug which demonstrated high in vitro and in vivo potency against Aβ42 peptide, reduced lipophilicity and enhanced brain free fraction compared to the previous series.

Application of PAMPA-models to predict BBB permeability including efflux ratio, plasma protein binding and physicochemical parameters.

This study examines whether algorithms to predict brain penetration of 88 drug candidates could benefit from inclusion of PAMPA data such as Peff, flux and membrane retention. Specifically the ability to fit experimentally derived LogBB data with PAMPA information and compound related physicochemical and structural parameters was assessed. Collected data were analyzed by partial least square analysis and various regression models for LogBB.

Study of T cell subsets in patients with cutaneous leishmaniasis.

The proportion of T lymphocyte populations was assessed using monoclonal antibodies (OKT3, OKT4, OKT8) and spontaneous E-rosette tests with SRBC (for total and active TE cells) in 36 patients with cutaneous leishmaniasis subdivided according to the clinical variety. The T cell profile was normal in patients with simple cutaneous leishmaniasis of early ulcerative type whereas active TE cells and OKT4 positive cells were reduced in some cases of late ulcerative type. A significant reduction of active TE cells and of OKT4 positive cells (helper/inducer phenotype) and increase of OKT8 positive cells (suppressor/cytotoxic phenotype) was observed in peripheral blood of all patients with persistent active lesions and leishmaniasis recidivans.