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Start Over Author "Gobeau N" Publisher american chemical society
2 results on '"Gobeau N"'

1. Setting Our Sights on Infectious Diseases

Author

De Rycker, M, Horn, D, Aldridge, B, Amewu, RK, Barry, CE, Buckner, FS, Cook, S, Ferguson, MAJ, Gobeau, N, Herrmann, J, Herding, P, Hope, W, Keiser, J, Lafuente-Monasterio, MJ, Leeson, PD, Leroy, D, Manjunatha, UH, McCarthy, J, Miles, TJ, Mizrahi, V, Moshynets, O, Niles, J, Overington, JP, Pottage, J, Rao, SPS, Read, KD, Ribeiro, I, Silver, LL, Southern, J, Spangenberg, T, Sundar, S, Taylor, C, Van Voorhis, W, White, NJ, Wyllie, S, Wyatt, PG, Gilbert, IH, De Rycker, M, Horn, D, Aldridge, B, Amewu, RK, Barry, CE, Buckner, FS, Cook, S, Ferguson, MAJ, Gobeau, N, Herrmann, J, Herding, P, Hope, W, Keiser, J, Lafuente-Monasterio, MJ, Leeson, PD, Leroy, D, Manjunatha, UH, McCarthy, J, Miles, TJ, Mizrahi, V, Moshynets, O, Niles, J, Overington, JP, Pottage, J, Rao, SPS, Read, KD, Ribeiro, I, Silver, LL, Southern, J, Spangenberg, T, Sundar, S, Taylor, C, Van Voorhis, W, White, NJ, Wyllie, S, Wyatt, PG, and Gilbert, IH

Abstract

In May 2019, the Wellcome Centre for Anti-Infectives Research (WCAIR) at the University of Dundee, UK, held an international conference with the aim of discussing some key questions around discovering new medicines for infectious diseases and a particular focus on diseases affecting Low and Middle Income Countries. There is an urgent need for new drugs to treat most infectious diseases. We were keen to see if there were lessons that we could learn across different disease areas and between the preclinical and clinical phases with the aim of exploring how we can improve and speed up the drug discovery, translational, and clinical development processes. We started with an introductory session on the current situation and then worked backward from clinical development to combination therapy, pharmacokinetic/pharmacodynamic (PK/PD) studies, drug discovery pathways, and new starting points and targets. This Viewpoint aims to capture some of the learnings.

Published
2020

2. Structure-Based and Property-Driven Optimization of N -Aryl Imidazoles toward Potent and Selective Oral RORγt Inhibitors.

Author

Hoegenauer K, Kallen J, Jiménez-Núñez E, Strang R, Ertl P, Cooke NG, Hintermann S, Voegtle M, Betschart C, McKay DJJ, Wagner J, Ottl J, Beerli C, Billich A, Dawson J, Kaupmann K, Streiff M, Gobeau N, Harlfinger S, Stringer R, and Guntermann C

Subjects
Administration, Oral, Animals, Dose-Response Relationship, Drug, Drug Design, Female, Fluorescence Resonance Energy Transfer, Half-Life, Imidazoles chemistry, Imidazoles pharmacokinetics, Male, Models, Molecular, Molecular Structure, Rats, Hypersensitivity, Delayed drug therapy, Imidazoles pharmacology, Nuclear Receptor Subfamily 1, Group F, Member 3 antagonists & inhibitors
Abstract

Retinoic acid receptor-related orphan receptor gamma-t (RORγt) is considered to be the master transcription factor for the development of Th17 cells that produce proinflammatory cytokines such as IL-17A. Overproportionate Th17 cell abundance is associated with the pathogenesis of many inflammatory conditions including psoriasis. In a high-throughput fluorescence resonance energy transfer (FRET) screen, we identified compound 1 as a hit with promising lipophilic efficiency (LipE). Using structure-based drug design based on a number of X-ray cocrystal structures, we morphed this hit class into potent imidazoles, exemplified by compound 3 . To improve the poor absorption, distribution, metabolism, and excretion (ADME) properties of neutral imidazoles, we extended our ligands with carboxylic acid substituents toward a polar, water-rich area of the protein. This highly lipophilicity-efficient modification ultimately led to the discovery of compound 14 , a potent and selective inhibitor of RORγt with good ADME properties and excellent in vivo pharmacokinetics. This compound showed good efficacy in an in vivo delayed-type hypersensitivity pharmacology model in rats.

Published
2019
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