Process Development and Scale-Up for the Preparation of the 1‑Methyl-quinazoline-2,4-dione Wnt Inhibitor SEN461

A practical and scalable route to the Wnt inhibitor SEN461 <b>1</b> is described herein. The optimized route consists of nine chemical steps. The intermediates are solids and were isolated by filtrations. Critical reactions steps in the medicinal chemistry route were modified for an initial scale-up process, and as a result, we developed a synthetic procedure for the preparation of multihundred gram quantities of the final product. A further process development for the phase 1 clinical batch campaign is reported

Development of a Scalable Route to the SMO Receptor Antagonist SEN794

A practical and scalable route to the SMO receptor antagonist SEN794 <b>1</b> is described herein. A new and efficient access to the key intermediate <b>7</b> via the Kröhnke reaction was developed, significantly simplifying the synthesis and reducing costs. The optimized route consists of six chemical steps plus a palladium scavenging step. The intermediates are solids and were isolated by filtrations, except for ester <b>9</b>, which was telescoped as the crude oil into the subsequent step. In the final amide formation step, target compound <b>1</b> was conveniently crystallized from the reaction mixture in high purity

Multifunctional Cholinesterase and Amyloid Beta Fibrillization Modulators. Synthesis and Biological Investigation

In order to identify novel Alzheimer’s modifying pharmacological tools, we developed bis-tacrines bearing a peptide moiety for specific interference with surface sites of <i>human</i> acetylcholinesterase (<i>h</i>AChE) binding amyloid-beta (Aβ). Accordingly, compounds <b>2a</b>–<b>c</b> proved to be inhibitors of <i>h</i>AChE catalytic and noncatalytic functions, binding the catalytic and peripheral sites, interfering with Aβ aggregation and with the Aβ self-oligomerization process (<b>2a</b>). Compounds <b>2a</b>–<b>c</b> in complex with <i>Tc</i>AChE span the gorge with the bis-tacrine system, and the peptide moieties bulge outside the gorge in proximity of the peripheral site. These moieties are likely responsible for the observed reduction of <i>h</i>AChE-induced Aβ aggregation since they physically hamper Aβ binding to the enzyme surface. Moreover, <b>2a</b> was able to significantly interfere with Aβ self-oligomerization, while <b>2b</b>,<b>c</b> showed improved inhibition of <i>h</i>AChE-induced Aβ aggregation