Michael Eric Green

Design and synthesis of dihydrobenzofuran amides as orally bioavailable, centrally active γ-secretase modulators.

We report the discovery and optimization of a novel series of dihydrobenzofuran amides as γ-secretase modulators (GSMs). Strategies for aligning in vitro potency with drug-like physicochemical properties and good microsomal stability while avoiding P-gp mediated efflux are discussed. Lead compounds such as 35 and 43 have moderate to good in vitro potency and excellent selectivity against Notch. Good oral bioavailability was achieved as well as robust brain Aβ42 lowering activity at 100 mg/kg po dose.

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 51 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.

Total synthesis of pederin and analogues.

The search for the causitive agent for Paederis dermatitis, an inflammatory condition that results from contact with beetles of the Paederis family, resulted in the isolation of pederin (1).[1] Pederin subsequently inspired a substantial wave of investigation that led to the determination of its correct structure,[2] the observation of its potent cytotoxicity,[3] the postulation of protein synthesis inhibition as its likely mode of biological activity,[4] the identification of the 60S subunit of the ribosome as its potential biological target,[5] and the establishment of bacterial symbionts as its true biogenetic source.[6] Pederin’s interesting biological activity and challenging structural features have spawned significant synthetic efforts, resulting in several total, formal, and analog syntheses.[7] A noteworthy advance in pederin accessibility was recently disclosed by Rawal,[7f] who reported that pederin could be prepared through a 12 step (longest linear sequence) route. In accord with our interest in the pederin family of molecules,[8] we report our total synthesis of 1. In addition to the brief linear sequence, this approach highlights the utility of a late stage multicomponent construction of the N-acylaminal structure that allows for the efficient construction of analogs with structural variation in each of three distinct subunits.

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 Alzheimers 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 sp(3)-character. The lead compound 21 (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.