Navigating from cellular phenotypic screen to clinical candidate: selective targeting of the NLRP3 inflammasome.

The NLRP3 inflammasome plays a pivotal role in host defense and drives inflammation against microbial threats, crystals, and danger-associated molecular patterns (DAMPs). Dysregulation of NLRP3 activity is associated with various human diseases, making it an attractive therapeutic target. Patients with NLRP3 mutations suffer from Cryopyrin-Associated Periodic Syndrome (CAPS) emphasizing the clinical significance of modulating NLRP3.

Discovery of 6,7-Dihydropyrazolo[1,5-]pyrazin-4(5)-one Derivatives as mGluR Negative Allosteric Modulators with Activity in a Rodent's Model of Cognition.

Allosteric modulators of the metabotropic group II receptors, mGluR and mGluR, have been widely explored due to their ability to modulate cognitive and neurological functions in mood disorders, although none have been approved yet. In our search for new and selective mGluR negative allosteric modulators (NAMs), series of 6,7-dihydropyrazolo[1,5-]pyrazin-4(5)-one derivatives were identified from our published series of 1,3,5-trisubstituted pyrazoles. SAR evolution of the initial hit resulted in 100-fold improvement in the mGluR NAM potency and subsequent selection of compound based on its overall profile, including selectivity and ADMET properties.

Scaffold Hopping to Imidazo[1,2-]pyrazin-8-one Positive Allosteric Modulators of Metabotropic Glutamate 2 Receptor.

Glutamate hyperfunction is implicated in multiple neurological and psychiatric diseases. Activation of the mGlu2 receptor results in reduced glutamate release and decreased excitability representing a promising novel therapeutic agent for the treatment of disorders such as epilepsy, schizophrenia, mood, anxiety, and other neuropsychiatric disorders. We have previously reported substantial efforts leading to potent and selective mGlu2 PAMs from different chemical series.

Diazaspirononane Nonsaccharide Inhibitors of O-GlcNAcase (OGA) for the Treatment of Neurodegenerative Disorders.

O-GlcNAcylation is a post-translational modification of tau understood to lower the speed and yield of its aggregation, a pathological hallmark of Alzheimer's disease (AD). O-GlcNAcase (OGA) is the only enzyme that removes O-linked -acetyl-d-glucosamine (O-GlcNAc) from target proteins. Therefore, inhibition of OGA represents a potential approach for the treatment of AD by preserving the O-GlcNAcylated tau protein.

Spiro-oxindole Piperidines and 3-(Azetidin-3-yl)-1-benzimidazol-2-ones as mGlu Receptor PAMs.

Starting from two weak mGlu receptor positive allosteric modulator (PAM) HTS hits ( and ), a molecular hybridization strategy resulted in the identification of a novel spiro-oxindole piperidine series with improved activity and metabolic stability. Scaffold hopping around the spiro-oxindole core identified the 3-(azetidin-3-yl)-1-benzimidazol-2-one as bioisoster. Medicinal chemistry optimization of these two novel chemotypes resulted in the identification of potent, selective, orally bioavailable, and brain penetrant mGluR PAMs.

Optimization of 1,4-Oxazine β-Secretase 1 (BACE1) Inhibitors Toward a Clinical Candidate.

In previous studies, the introduction of electron withdrawing groups to 1,4-oxazine BACE1 inhibitors reduced the p K of the amidine group, resulting in compound 2 that showed excellent in vivo efficacy, lowering Aβ levels in brain and CSF. However, a suboptimal cardiovascular safety margin, based on QTc prolongation, prevented further progression. Further optimization resulted in the replacement of the 2-fluoro substituent by a CF-group, which reduced hERG inhibition.

1,4-Oxazine β-Secretase 1 (BACE1) Inhibitors: From Hit Generation to Orally Bioavailable Brain Penetrant Leads.

1,4-Oxazines are presented, which show good in vitro inhibition in enzymatic and cellular BACE1 assays. We describe lead optimization focused on reducing the amidine pKa while optimizing interactions in the BACE1 active site. Our strategy permitted modulation of properties such as permeation and especially P-glycoprotein efflux.