Protocol for the Direct Conversion of Lactones to Lactams Mediated by 1,5,7-Triazabicyclo[4.4.0]dec-5-ene: Synthesis of Pyridopyrazine-1,6-diones

We present an operationally simple lactone-to-lactam transformation utilizing diverse amine nucleophiles. The key steps of amidation, alcohol activation, and cyclization are all mediated by one reagent (TBD) in a single vessel at room temperature. We illustrate the convenience of this protocol by synthesizing a wide range of <i>N</i>-alkyl, <i>N</i>-aryl, and <i>N</i>-hetereoaryl pyridopyrazine-1,6-diones, an important class of medicinally significant lactams. Furthermore, the reported methodology can be applied to the synthesis of milligram to hundred gram quantities of pyridopyrazine-1,6-diones without the use of specialized equipment

Discovery of cyclopropyl chromane-derived pyridopyrazine-1,6-dione γ-secretase modulators with robust central efficacy† †Electronic supplementary information (ESI) available. CCDC 1452774. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6md00406g

γ-Secretase modulators for the treatment of Alzheimer's disease. Herein we describe the discovery of a novel series of cyclopropyl chromane-derived pyridopyrazine-1,6-dione γ-secretase modulators for the treatment of Alzheimer's disease (AD). Using ligand-based design tactics such as conformational analysis and molecular modeling, a cyclopropyl chromane unit was identified as a suitable heterocyclic replacement for a naphthyl moiety that was present in the preliminary lead 4 . The optimized lead molecule 44 achieved good central exposure resulting in robust and sustained reduction of brain amyloid-β42 (Aβ42) when dosed orally at 10 mg kg –1 in a rat time-course study. Application of the unpaced isolated heart Langendorff model enabled efficient differentiation of compounds with respect to cardiovascular safety, highlighting how minor structural changes can greatly impact the safety profile within a series of compounds

Design, Synthesis, and Pharmacological Evaluation of a Novel Series of Pyridopyrazine-1,6-dione γ‑Secretase Modulators

Herein we describe the design and synthesis of a novel series of γ-secretase modulators (GSMs) that incorporates a pyridopiperazine-1,6-dione ring system. To align improved potency with favorable ADME and in vitro safety, we applied prospective physicochemical property-driven design coupled with parallel medicinal chemistry techniques to arrive at a novel series containing a conformationally restricted core. Lead compound <b>51</b> exhibited good in vitro potency and ADME, which translated into a favorable in vivo pharmacokinetic profile. Furthermore, robust reduction of brain Aβ42 was observed in guinea pig at 30 mg/kg dosed orally. Through chemical biology efforts involving the design and synthesis of a clickable photoreactive probe, we demonstrated specific labeling of the presenilin N-terminal fragment (PS1-NTF) within the γ-secretase complex, thus gaining insight into the binding site of this series of GSMs

Design of Pyridopyrazine-1,6-dione γ‑Secretase Modulators that Align Potency, MDR Efflux Ratio, and Metabolic Stability

Herein we describe the design and synthesis of a series of pyridopyrazine-1,6-dione γ-secretase modulators (GSMs) for Alzheimer’s disease (AD) that achieve good alignment of potency, metabolic stability, and low MDR efflux ratios, while also maintaining favorable physicochemical properties. Specifically, incorporation of fluorine enabled design of metabolically less liable lipophilic alkyl substituents to increase potency without compromising the sp³-character. The lead compound <b>21</b> (PF-06442609) displayed a favorable rodent pharmacokinetic profile, and robust reductions of brain Aβ42 and Aβ40 were observed in a guinea pig time-course experiment