Florian Wakenhut

Design and Synthesis of a Pan-Janus Kinase Inhibitor Clinical Candidate (PF-06263276) Suitable for Inhaled and Topical Delivery for the Treatment of Inflammatory Diseases of the Lungs and Skin

Peter Jones, Richard Storer, Yogesh Sabnis, Florian Wakenhut et autres

By use of a structure-based computational method for identification of structurally novel Janus kinase (JAK) inhibitors predicted to bind beyond the ATP binding site, a potent series of indazoles was identified as selective pan-JAK inhibitors with a type 1.5 binding mode. Optimization …

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The Discovery of Potent Nonstructural Protein 5A (NS5A) Inhibitors with a Unique Resistance Profile—Part 1

Thien Duc Tran, Florian Wakenhut, Chris Pickford, Stephen M. Shaw et autres

Nonstructural protein 5A (NS5A) represents a novel target for the treatment of hepatitis C virus (HCV). Daclatasvir, recently reported by Bristol-Myers-Squibb, is a potent NS5A inhibitor currently under investigation in phase 3 clinical trials. While the performance of daclatasvir has been impressive, …

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The Discovery of Potent Nonstructural Protein 5A (NS5A) Inhibitors with a Unique Resistance Profile—Part 2

Florian Wakenhut, Thien Duc Tran, Chris Pickford, Stephen M. Shaw et autres

Abstract In ongoing studies towards novel hepatitis C virus (HCV) therapeutics, inhibitors of nonstructural protein 5A (NS5A) were evaluated. Specifically, starting from previously reported lead compounds, peripheral substitution patterns of a series of biaryl‐linked pyrrolidine NS5A replication complex inhibitors were probed and …

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Cytoprotection by omega-3 fatty acids as a therapeutic drug vehicle when combined with nephrotoxic drugs in an intravenous emulsion: Effects on intraglomerular mesangial cells

Gabriel A. Bonaterra, Florian Wakenhut, Doris Röthlein, M. Wolf et autres

During therapeutic interventions, blood concentrations of intravenously applied drugs are higher, and their onset of pharmacological action is faster than with other routes of drug administration. However, acute drug therapy often produces nephrotoxic side effects, as commonly seen after treatment with Ketorolac …

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ChemInform Abstract: Palladium‐Catalyzed Synthesis of Benzimidazoles and Quinazolinones from Common Precursors.

Jessie E. R. Sadig, Radleigh A. A. Foster, Florian Wakenhut, Michael C. Willis

Abstract Both pathways, which produce the desired N‐heterocyclic skeletons, tolerate a broad spectrum of functionalities.

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Palladium-Catalyzed Synthesis of Benzimidazoles and Quinazolinones from Common Precursors

Jessie E. R. Sadig, Radleigh A. A. Foster, Florian Wakenhut, Michael C. Willis

N-(o-Halophenyl)imidoyl chlorides and the corresponding imidates are easily prepared and can be utilized as complementary precursors for the synthesis of important heterocycles. The synthesis of N-substituted benzimidazoles was possible from the palladium-catalyzed reaction of both classes of substrate with a variety of …

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Small Molecules Targeting Hepatitis C Virus-Encoded NS5A Cause Subcellular Redistribution of Their Target: Insights into Compound Modes of Action

Paul Targett‐Adams, Emily J. S. Graham, Jenny Middleton, Amy E. Palmer et autres

The current standard of care for hepatitis C virus (HCV)-infected patients consists of lengthy treatment with interferon and ribavirin. To increase the effectiveness of HCV therapy, future regimens will incorporate multiple direct-acting antiviral (DAA) drugs. Recently, the HCV-encoded NS5A protein has emerged …

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Intramolecular hydrogen bonding to improve membrane permeability and absorption in beyond rule of five chemical space

Alexander Alex, David S. Millan, Manuel Pérez, Florian Wakenhut et autres

Utilising ‘beyond rule of five’ chemical space is becoming increasingly important in drug design, but is usually at odds with good oral absorption. The formation of intramolecular hydrogen bonds in drug molecules is hypothesised to shield polarity facilitating improved membrane permeability and …

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In-cell click labelling of small molecules to determine subcellular localisation

Lyn H. Jones, David M. Beal, Matthew D. Selby, Owen Everson et autres

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A Case History on the Challenges of Central Nervous System and Dual Pharmacology Drug Discovery

Paul V. Fish, Anthony Harrison, Florian Wakenhut, Gavin A. Whitlock

This chapter describes the case history of a drug discovery project targeting a centrally penetrant, dual serotonin/noradrenaline reuptake inhibitor (SNRI) for the treatment of stress urinary incontinence, and highlights how key drug-like properties required for the discovery, and progression of a candidate …

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Second generation N-(1,2-diphenylethyl)piperazines as dual serotonin and noradrenaline reuptake inhibitors: Improving metabolic stability and reducing ion channel activity

M. Jonathan Fray, Paul V. Fish, Gillian A. Allan, Gerwyn Bish et autres

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N-[(3S)-Pyrrolidin-3-yl]benzamides as novel dual serotonin and noradrenaline reuptake inhibitors: Impact of small structural modifications on P-gp recognition and CNS penetration (vol 19, pg 5078, 2009)

Florian Wakenhut, PV Fish, M. Jonathan Fray, Harrison Ac et autres