Design and Synthesis of Inhibitors of the E3 Ligase SMAD Specific E3 Ubiquitin Protein Ligase 1 as a Treatment for Lung Remodeling in Pulmonary Arterial HypertensionClick to copy article linkArticle link copied!
- Duncan E. Shaw*Duncan E. Shaw*Email: [email protected]Novartis Institutes of Biomedical Research (NIBR), 250 Massachusetts Avenue, Cambridge Massachusetts 01239, United StatesMore by Duncan E. Shaw
- Nichola SmithNichola SmithNovartis Institutes of Biomedical Research (NIBR), 250 Massachusetts Avenue, Cambridge Massachusetts 01239, United StatesMore by Nichola Smith
- Rene Beerli
- Simona Cotesta
- Pier-Luca D’AlessandroPier-Luca D’AlessandroNIBR Basel Fabrikstrasse 2, 4056 Basel, SwitzerlandMore by Pier-Luca D’Alessandro
- Anne-Marie EdwardsAnne-Marie EdwardsNIBR, Wimblehurst Road, Horsham West Sussex RH12 5AB, U.K.More by Anne-Marie Edwards
- Rene Lattmann
- Dimitrios Lizos
- Robert Pulz
- Lisa Rooney
- Bindi Sohal
- Caroline Rynn
- Jessica Taylor
- Thomas Troxler
- Gareth Williams
- Sabine Guth
- David RowlandsDavid RowlandsNovartis Institutes of Biomedical Research (NIBR), 250 Massachusetts Avenue, Cambridge Massachusetts 01239, United StatesMore by David Rowlands
Abstract
Pulmonary arterial hypertension (PAH) is a devastating rare disease, which despite currently available treatments, still represents a high unmet medical need. Specific E3 ubiquitin protein ligase 1 (SMURF1) is a HECT E3 ligase that ubiquitinates key signaling molecules from the TGFβ/BMP pathways, which are of great relevance in the pathophysiology of PAH. Herein, the design and synthesis of novel potent small-molecule SMURF1 ligase inhibitors are described. Lead molecule 38 has demonstrated good oral pharmacokinetics in rats and significant efficacy in a rodent model of pulmonary hypertension.
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This article is cited by 6 publications.
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- Franca M. Cordero, Donatella Giomi, Fabrizio Machetti. Five-membered ring systems with O and N atoms. 2024, 275-308. https://doi.org/10.1016/B978-0-443-33494-8.00020-2
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