Wei Lemaire

Fluorinated Isoindolinone-Based Glucosylceramide Synthase Inhibitors with Low Human Dose Projections

H. Marie Loughran, Kathy M. Schirripa, Anthony J. Roecker, Michael J. Breslin et autres

Inhibition of glucosylceramide synthase (GCS) has been proposed as a therapeutic strategy for the treatment of Parkinson’s Disease (PD), particularly in patients where glycosphingolipid accumulation and lysosomal impairment are thought to be contributing to disease progression. Herein, we report the late-stage optimization …

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Virtual screening for early identification of potent and selective histone deacetylase 6 inhibitor series

Shawn J. Stachel, Deping Wang, Anthony T. Ginnetti, Shahriar Niroomand et autres

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Pyrazole Ureas as Low Dose, CNS Penetrant Glucosylceramide Synthase Inhibitors for the Treatment of Parkinson’s Disease

Anthony J. Roecker, Kathy M. Schirripa, H. Marie Loughran, Ling Tong et autres

Parkinson’s disease is the second most prevalent progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra. Loss-of-function mutations in GBA, the gene that encodes for the lysosomal enzyme glucosylcerebrosidase, are a major genetic risk factor for the …

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Virtual Screening for Early Identification of Potent and Selective Histone Deacetylase 6 Inhibitor Series

Shawn J. Stachel, Deping Wang, Anthony T. Ginnetti, Shahriar Niroomand et autres

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A novel glucosylceramide synthase inhibitor attenuates alpha synuclein pathology and lysosomal dysfunction in preclinical models of synucleinopathy

Mali L. Cosden, Sarah Jinn, Lihang Yao, Cheryl A. Gretzula et autres

Mutations in the lysosomal enzyme glucocerebrosidase (GCase, GBA1 gene) are the most common genetic risk factor for developing Parkinson's disease (PD). GCase metabolizes the glycosphingolipids glucosylceramide (GlcCer) and glucosylsphingosine (GlcSph). Mutations in GBA1 reduce enzyme activity and the resulting accumulation of glycosphingolipids …

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Redefining the Histone Deacetylase Inhibitor Pharmacophore: High Potency with No Zinc Cofactor Interaction

Douglas C. Beshore, Gregory C. Adam, Richard J. O. Barnard, Christine Burlein et autres

A novel series of histone deacetylase (HDAC) inhibitors lacking a zinc-binding moiety has been developed and described herein. HDAC isozyme profiling and kinetic studies indicate that these inhibitors display a selectivity preference for HDACs 1, 2, 3, 10, and 11 via a …

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Kinetic Analysis of Membrane Potential Dye Response to NaV1.7 Channel Activation Identifies Antagonists with Pharmacological Selectivity against NaV1.5

Michael Finley, Jason Cassaday, Tony Kreamer, Xin-Nian Li et autres

The NaV1.7 voltage-gated sodium channel is a highly valued target for the treatment of neuropathic pain due to its expression in pain-sensing neurons and human genetic mutations in the gene encoding NaV1.7, resulting in either loss-of-function (e.g., congenital analgesia) or gain-of-function (e.g., …

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CCDC 1445355: Experimental Crystal Structure Determination

Anthony J. Roecker, Swati P. Mercer, Jeffrey M. Bergman, Kevin F. Gilbert et autres

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, …

Discovery of diazepane amide DORAs and 2-SORAs enabled by exploration of isosteric quinazoline replacements

Anthony J. Roecker, Swati P. Mercer, Jeffrey M. Bergman, Kevin F. Gilbert et autres

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Discovery of piperidine ethers as selective orexin receptor antagonists (SORAs) inspired by filorexant

Izzat T. Raheem, Michael J. Breslin, Joseph G. Bruno, Tamara D. Cabalu et autres

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Discovery of MK-3697: A selective orexin 2 receptor antagonist (2-SORA) for the treatment of insomnia

Anthony J. Roecker, Thomas S. Reger, M. Christa Mattern, Swati P. Mercer et autres

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Discovery of dual orexin receptor antagonists with rat sleep efficacy enabled by expansion of the acetonitrile-assisted/diphosgene-mediated 2,4-dichloropyrimidine synthesis

Anthony J. Roecker, Swati P. Mercer, C. Meacham Harrell, Susan L. Garson et autres

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