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Step-economic and scalable syntheses of novel thia-azaspiro[3.4]octanes are reported. These spirocycles and some related intermediates can serve as uncharted multifunctional modules for drug discovery chemistry. [ABSTRACT FROM AUTHOR]

The application of the evolutionary fragment-based de novo design tool TOPology Assigning System (TOPAS), starting from a known CB1R (CB-1 receptor) ligand, followed by further refinement principles, including pharmacophore compliance, chemical tractability, and drug likeness, allowed the identification of benzodioxoles as a novel CB1R inverse agonist series. Extensive multidimensional optimization was rewarded by the identification of promising lead compounds, showing in vivo activity. These compounds reversed the CP-55940-induced hypothermia in Naval Medical Research Institute (NMRI) mice and reduced body-weight gain, as well as fat mass, in diet-induced obese Sprague−Dawley rats. Herein, we disclose the tools and strategies that were employed for rapid hit identification, synthesis and generation of structure−activity relationships, ultimately leading to the identification of (+)-[( R)-2-(2,4-dichloride-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone ( R)-14g . Biochemical, pharmacokinetic, and pharmacodynamic characteristics of ( R)-14g are discussed. [ABSTRACT FROM AUTHOR]

A multi-parallel enzyme screen has been used to identify potential catalysts for the selective hydrolysis of diastereomeric esters and then subsequently applied in their separation upon scaleup. [ABSTRACT FROM AUTHOR]