Douglas C. Beshore

Evaluation of a non-nucleoside inhibitor of the RSV RNA-dependent RNA polymerase in translatable animals models

Michael P. Citron, Xiaowei Zang, Andrew Leithead, Meng Shi et autres

Respiratory Syncytial Virus (RSV) causes severe respiratory infections and concomitant disease resulting in significant morbidity and mortality in infants, elderly, and immunocompromised adults. Vaccines, monoclonal antibodies, and small-molecule antivirals are now either available or in development to prevent and treat RSV infections. …

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Rapid Affinity and Microsomal Stability Ranking of Crude Mixture Libraries of Histone Deacetylase Inhibitors

Sriram Tyagarajan, Christine L. Andrews, Douglas C. Beshore, Alexei V. Buevich et autres

The science of drug discovery involves multiparameter optimization of molecular structures through iterative design-make-test cycles. For medicinal chemistry library synthesis, traditional workflows involve the isolation of each individual compound, gravimetric quantitation, and preparation of a standard concentration solution for biological assays. In …

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Cerastecin Inhibition of the Lipooligosaccharide Transporter MsbA to Combat Acinetobacter baumannii: From Screening Impurity to In Vivo Efficacy

Jason W. Skudlarek, Andrew Cooke, Helen J. Mitchell, Kerim Babaoglu et autres

Acinetobacter baumannii, a commonly multidrug-resistant Gram-negative bacterium responsible for large numbers of bloodstream and lung infections worldwide, is increasingly difficult to treat and constitutes a growing threat to human health. Structurally novel antibacterial chemical matter that can evade existing resistance mechanisms is …

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Conserved allosteric inhibitory site on the respiratory syncytial virus and human metapneumovirus RNA-dependent RNA polymerases

Victoria A. Kleiner, Thierry O. Fischmann, John A. Howe, Douglas C. Beshore et autres

Abstract Respiratory syncytial virus (RSV) and human metapneumovirus (HMPV) are related RNA viruses responsible for severe respiratory infections and resulting disease in infants, elderly, and immunocompromised adults 1–3 . Therapeutic small molecule inhibitors that bind to the RSV polymerase and inhibit viral …

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A Phenotypic Screen Identifies Potent DPP9 Inhibitors Capable of Killing HIV-1 Infected Cells

Keith P. Moore, Adam G. Schwaid, Matthew Tudor, Sang‐Ho Park et autres

Although current antiretroviral therapy can control HIV-1 replication and prevent disease progression, it is not curative. Identifying mechanisms that can lead to eradication of persistent viral reservoirs in people living with HIV-1 (PLWH) remains an outstanding challenge to achieving cure. Utilizing a …

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Building a Culture of Medicinal Chemistry Knowledge Sharing

Douglas C. Beshore, Andrew M. Haidle, Ashok Arasappan, Yeon‐Hee Lim et autres

Increasing the efficiency of the drug discovery process is a challenge faced by drug hunters everywhere. One strategy medicinal chemists employ to meet this challenge is learning from knowledge sources within and beyond their organization. In this Perspective, we discuss the evolution …

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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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Discovery of ethyl ketone-based HDACs 1, 2, and 3 selective inhibitors for HIV latency reactivation

Wensheng Yu, Jian Liu, Younong Yu, Vivian Zhang et autres

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Microbial biotransformation – an important tool for the study of drug metabolism

Rhys Salter, Douglas C. Beshore, Steven L. Colletti, Liam Evans et autres

Metabolite identification is an integral part of both preclinical and clinical drug discovery and development. Synthesis of drug metabolites is often required to support definitive identification, preclinical safety studies and clinical trials. Here we describe the use of microbial biotransformation as a …

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MK-7622: A First-in-Class M 1 Positive Allosteric Modulator Development Candidate

Douglas C. Beshore, Christina Ng Di Marco, Ronald K. Chang, Thomas J. Greshock et autres

Identification of ligands that selectively activate the M 1 muscarinic signaling pathway has been sought for decades to treat a range of neurological and cognitive disorders. Herein, we describe the optimization efforts focused on addressing key physicochemical and safety properties, ultimately leading …

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Preclinical to Human Translational Pharmacology of the Novel M1 Positive Allosteric Modulator MK-7622

Jason M. Uslaner, Scott D. Kuduk, Marion Wittmann, Henry S. Lange et autres

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High-Throughput Agonist Shift Assay Development for the Analysis of M1-Positive Allosteric Modulators

Michelle F. Homsher, Douglas C. Beshore, Jason Cassaday, Brian Squadroni et autres

Agonist shift assays feature cross-titrations of allosteric modulators and orthosteric ligands. Information generated in agonist shift assays can include a modulator's effect on the orthosteric agonist's potency (alpha) and efficacy (beta), as well as direct agonist activity of the allosteric ligand (tauB) …

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