Discovery and optimization of an azetidine chemical series as a free fatty acid receptor 2 (FFA2) antagonist: from hit to clinic.

FFA2, also called GPR43, is a G-protein coupled receptor for short chain fatty acids which is involved in the mediation of inflammatory responses. A class of azetidines was developed as potent FFA2 antagonists. Multiparametric optimization of early hits with moderate potency and suboptimal ADME properties led to the identification of several compounds with nanomolar potency on the receptor combined with excellent pharmacokinetic (PK) parameters.

Rigid Analogues of Antimitotic Indolobenzazepinones: New Insights into Tubulin Binding via Molecular Modeling.

Two rigid analogues of 5-ethylindolobenzazepinone 4, a potent cytotoxic agent and inhibitor of tubulin polymerization, were prepared. The first was the indane derivative 5, in which the ethyl group is attached to the benzo moiety. The second was the pyrrolidine analogue 6, in which the ethyl chain was bound to the lactam nitrogen.

Marine Toxins with Spiroimine Rings: Total Synthesis of Pinnatoxin A.

This microreview provides a compilation of synthetic approaches and total syntheses of pinnatoxin A in a survey of the literature up to early 2010. Pinnatoxin A is the first discovered and representative member of a fascinating group of potent marine toxins that share a spiroimine subunit as a unifying structural element.

Valence tautomerism in titanium enolates: catalytic radical haloalkylation and application in the total synthesis of neodysidenin.

A direct ruthenium-catalyzed radical chloroalkylation of N-acyl oxazolidinones capitalizing on valence tautomerism of titanium enolates has been developed. The chloroalkylation method served as the centerpiece in the enantioselective total synthesis of trichloroleucine-derived marine natural product neodysidenin.

New C5-alkylated indolobenzazepinones acting as inhibitors of tubulin polymerization: cytotoxic and antitumor activities.

A series of 5-alkylindolobenzazepin-7-ones was synthesized by Suzuki coupling between 3-iodoindole-2-carboxylates and the appropriate alpha-alkylbenzylamino o-boronic acids followed by cyclization to the lactam. Derivatives having a linear alkyl chain at C5 were found to be highly cytotoxic to KB cells with IC50 values in the 30-80 nM range. These compounds also inhibited the polymerization of tubulin with IC50's of 1-2 microM.

Evaluation of two software tools dedicated to an automatic analysis of the CT scanner image spatial resolution.

An evaluation of two software tools dedicated to an automatic analysis of the CT scanner image spatial resolution is presented in this paper. The methods evaluated consist of calculating the Modulation Transfer Function (MTF) of the CT scanners; the first uses an image of an impulse source, while the second method proposed by Droege and Morin uses an image of cyclic bar patterns. Two Digital Test Objects (DTO) are created to this purpose.