Uncompetitive, adduct-forming SARM1 inhibitors are neuroprotective in preclinical models of nerve injury and disease.

Axon degeneration is an early pathological event in many neurological diseases. The identification of the nicotinamide adenine dinucleotide (NAD) hydrolase SARM1 as a central metabolic sensor and axon executioner presents an exciting opportunity to develop novel neuroprotective therapies that can prevent or halt the degenerative process, yet limited progress has been made on advancing efficacious inhibitors. We describe a class of NAD-dependent active-site SARM1 inhibitors that function by intercepting NAD hydrolysis and undergoing covalent conjugation with the reaction product adenosine diphosphate ribose (ADPR).

Structural and Mechanistic Regulation of the Pro-degenerative NAD Hydrolase SARM1.

The NADase SARM1 is a central switch in injury-activated axon degeneration, an early hallmark of many neurological diseases. Here, we present cryo-electron microscopy (cryo-EM) structures of autoinhibited (3.3 Å) and active SARM1 (6.

Molecular basis for the loss-of-function effects of the Alzheimer's disease-associated R47H variant of the immune receptor TREM2.

Triggering receptor expressed on myeloid cells 2 (TREM2) is an immune receptor expressed on the surface of microglia, macrophages, dendritic cells, and osteoclasts. The R47H TREM2 variant is a significant risk factor for late-onset Alzheimer's disease (AD), and the molecular basis of R47H TREM2 loss of function is an emerging area of TREM2 biology. Here, we report three high-resolution structures of the extracellular ligand-binding domains (ECDs) of R47H TREM2, apo-WT, and phosphatidylserine (PS)-bound WT TREM2 at 1.

TREM2-activating antibodies abrogate the negative pleiotropic effects of the Alzheimer's disease variant on murine myeloid cell function.

Triggering receptor expressed on myeloid cells 2 (TREM2) is an orphan immune receptor expressed on cells of myeloid lineage such as macrophages and microglia. The rare variant R47H TREM2 is associated with an increased risk for Alzheimer's disease, supporting the hypothesis that TREM2 loss of function may exacerbate disease progression. However, a complete knockout of the gene in different genetic models of neurodegenerative diseases has been reported to result in both protective and deleterious effects on disease-related end points and myeloid cell function.

Discovery of clinical candidate 1-(4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)ethanone (AMG 579), a potent, selective, and efficacious inhibitor of phosphodiesterase 10A (PDE10A).

We report the identification of a PDE10A clinical candidate by optimizing potency and in vivo efficacy of promising keto-benzimidazole leads 1 and 2. Significant increase in biochemical potency was observed when the saturated rings on morpholine 1 and N-acetyl piperazine 2 were changed by a single atom to tetrahydropyran 3 and N-acetyl piperidine 5. A second single atom modification from pyrazines 3 and 5 to pyridines 4 and 6 improved the inhibitory activity of 4 but not 6.

Discovery and optimization of a series of liver X receptor antagonists.

The present report describes our efforts to convert an existing LXR agonist into an LXR antagonist using a structure-based approach. A series of benzenesulfonamides was synthesized based on structural modification of a known LXR agonist and was determined to be potent dual liver X receptor (LXR α/β) ligands. Herein we report the identification of compound 54 as the first reported LXR antagonist that is suitable for pharmacological in vivo evaluation in rodents.

Discovery of a new binding mode for a series of liver X receptor agonists.

Structural modification of a series of dual LXRα/β agonists led to the identification of a new class of LXRβ partial agonists. An X-ray co-crystal structure shows that a representative member of this series, pyrrole 5, binds to LXRβ with a reversed orientation compared to 1.

G-protein-coupled receptor GPR21 knockout mice display improved glucose tolerance and increased insulin response.

GPR21 is an orphan G-protein-coupled receptor. We found that mice deficient for the GPR21 gene were resistant to diet-induced obesity. Knockout mice were leaner than their wildtype counterpart, despite that no difference was observed in food intake.

The G-protein-coupled receptor GPR103 regulates bone formation.

GPR103 is a G-protein-coupled receptor with reported expression in brain, heart, kidney, adrenal gland, retina, and testis. It encodes a 455-amino-acid protein homologous to neuropeptide FF2, neuropeptide Y2, and galanin GalR1 receptors. Its natural ligand was recently identified as 26RFa, a novel human RF-amide-related peptide with orexigenic activity.

Genetic inactivation of melanin-concentrating hormone receptor subtype 1 (MCHR1) in mice exerts anxiolytic-like behavioral effects.

The biological effects of the melanin-concentrating hormone (MCH) are mediated by the melanin concentrating hormone receptor 1 (MCHR1) in mice. This receptor is enriched in brain areas that are involved in the modulation of mood and affect, suggesting that MCH-dependent signaling may influence neurobiological mechanisms underlying fear and anxiety processes. To test this, we have generated mice lacking functional MCHR1 and characterized phenotypic traits using a number of behavioral tests.