Herein, we detail the optimization of the mGlu negative allosteric modulator (NAM), VU6001192, by a reductionist approach to afford a novel, simplified mGlu NAM scaffold. This new chemotype not only affords potent and selective mGlu inhibition, as exemplified by VU6001966 (mGlu IC = 78 nM, mGlu IC > 30 μM), but also excellent central nervous system (CNS) penetration ( = 1.9, = 0.78), a feature devoid in all previously disclosed mGlu NAMs (s ≈ 0.3, s ≈ 0.1). Moreover, this series, based on overall properties, represents an exciting lead series for potential mGlu PET tracer development.

Alzheimer’s disease (AD) is a progressive, neurodegenerative disorder that is characterized by neurodegeneration, cognitive impairment, and an eventual inability to perform daily tasks. The etiology of Alzheimer’s is complex, with numerous environmental and genetic factors contributing to the disease. Late-onset AD is highly heritable (60 to 80%), and over 40 risk loci for AD have been identified via large genome-wide association studies, most of which are common variants with small effect sizes. Although these discoveries have provided novel insight on biological contributors to AD, disease-modifying treatments remain elusive. Recently, the concepts of resistance to pathology and resilience against the downstream consequences of pathology have been of particular interest in the Alzheimer’s field as studies continue to identify individuals who evade the pathology of the disease even into late life and individuals who have all of the neuropathological features of AD but evade downstream neurodegeneration and cognitive impairment. It has been hypothesized that a shift in focus from Alzheimer’s risk to resilience presents an opportunity to uncover novel biological mechanisms of AD and to identify promising therapeutic targets for the disease. This review will highlight a selection of genes and variants that have been reported to confer protection from AD within the literature and will also discuss evidence for the biological underpinnings behind their protective effect with a focus on genes involved in lipid metabolism, cellular trafficking, endosomal and lysosomal function, synaptic function, and inflammation. Finally, we offer some recommendations in areas where the field can rapidly advance towards precision interventions that leverage the ideas of protection and resilience for the development of novel therapeutic strategies.

Herein, we report the structure-activity relationships within a series of potent, selective, and orally bioavailable muscarinic acetylcholine receptor 4 (M) positive allosteric modulators (PAMs). Compound (VU0467485) possesses robust M PAM potency across species and efficacy in preclinical models of schizophrenia. Coupled with an attractive DMPK profile and suitable predicted human PK, (VU0467485) was evaluated as a preclinical development candidate.

Herein, we detail the optimization of the mGlu NAM, VU0650786, via a reductionist approach to afford a novel, simplified mGlu NAM scaffold that engenders potent and selective mGlu inhibition (mGlu IC = 245 nM, mGlu IC > 30 μM) with excellent central nervous system penetration (rat brain/plasma = 1.2, = 0.40). Moreover, this new chemotype, exemplified by VU6010572, requires only four synthetic steps and displays improved physiochemical properties and efficacy in a mouse tail suspension test (MED = 3 mg/kg i.p.).