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Discovery and Optimization of the First Highly Effective and Orally Available Galectin-3 Inhibitors for Treatment of Fibrotic Disease

Zetterberg, Fredrik R. ; Mackinnon, Alison ; Brimert, Thomas ; Gravelle, Lise ; Johnsson, Richard E. ; Kahl-Knutson, Barbro LU ; Leffler, Hakon LU ; Nilsson, Ulf J. LU ; Pedersen, Anders and Peterson, Kristoffer LU , et al. (2022) In Journal of Medicinal Chemistry 65(19). p.12626-12638
Abstract

Galectin-3 is a carbohydrate-binding protein central to regulating mechanisms of diseases such as fibrosis, cancer, metabolic, inflammatory, and heart disease. We recently found a high affinity (nM) thiodigalactoside GB0139 which currently is in clinical development (PhIIb) as an inhaled treatment of idiopathic pulmonary fibrosis. To enable treatment of systemically galectin-3 driven disease, we here present the first series of selective galectin-3 inhibitors combining high affinity (nM) with oral bioavailability. This was achieved by optimizing galectin-3 specificity and physical chemical parameters for a series of disubstituted monogalactosides. Further characterization showed that this class of compounds reduced profibrotic gene... (More)

Galectin-3 is a carbohydrate-binding protein central to regulating mechanisms of diseases such as fibrosis, cancer, metabolic, inflammatory, and heart disease. We recently found a high affinity (nM) thiodigalactoside GB0139 which currently is in clinical development (PhIIb) as an inhaled treatment of idiopathic pulmonary fibrosis. To enable treatment of systemically galectin-3 driven disease, we here present the first series of selective galectin-3 inhibitors combining high affinity (nM) with oral bioavailability. This was achieved by optimizing galectin-3 specificity and physical chemical parameters for a series of disubstituted monogalactosides. Further characterization showed that this class of compounds reduced profibrotic gene expression in liver myofibroblasts and displayed antifibrotic activity in CCl4-induced liver fibrosis and bleomycin-induced lung fibrosis mouse models. On the basis of the overall pharmacokinetic, pharmacodynamic, and safety profile, GB1211 was selected as the clinical candidate and is currently in phase IIa clinical trials as a potential therapy for liver cirrhosis and cancer.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Medicinal Chemistry
volume
65
issue
19
pages
13 pages
publisher
The American Chemical Society (ACS)
external identifiers
  • pmid:36154172
  • scopus:85139212115
ISSN
0022-2623
DOI
10.1021/acs.jmedchem.2c00660
language
English
LU publication?
yes
id
ac3ac298-1ed7-49cc-9f21-1e3ceec255cf
date added to LUP
2022-12-14 13:07:51
date last changed
2025-03-18 23:56:56
@article{ac3ac298-1ed7-49cc-9f21-1e3ceec255cf,
  abstract     = {{<p>Galectin-3 is a carbohydrate-binding protein central to regulating mechanisms of diseases such as fibrosis, cancer, metabolic, inflammatory, and heart disease. We recently found a high affinity (nM) thiodigalactoside GB0139 which currently is in clinical development (PhIIb) as an inhaled treatment of idiopathic pulmonary fibrosis. To enable treatment of systemically galectin-3 driven disease, we here present the first series of selective galectin-3 inhibitors combining high affinity (nM) with oral bioavailability. This was achieved by optimizing galectin-3 specificity and physical chemical parameters for a series of disubstituted monogalactosides. Further characterization showed that this class of compounds reduced profibrotic gene expression in liver myofibroblasts and displayed antifibrotic activity in CCl4-induced liver fibrosis and bleomycin-induced lung fibrosis mouse models. On the basis of the overall pharmacokinetic, pharmacodynamic, and safety profile, GB1211 was selected as the clinical candidate and is currently in phase IIa clinical trials as a potential therapy for liver cirrhosis and cancer.</p>}},
  author       = {{Zetterberg, Fredrik R. and Mackinnon, Alison and Brimert, Thomas and Gravelle, Lise and Johnsson, Richard E. and Kahl-Knutson, Barbro and Leffler, Hakon and Nilsson, Ulf J. and Pedersen, Anders and Peterson, Kristoffer and Roper, James A. and Schambye, Hans and Slack, Robert J. and Tantawi, Susan}},
  issn         = {{0022-2623}},
  language     = {{eng}},
  month        = {{10}},
  number       = {{19}},
  pages        = {{12626--12638}},
  publisher    = {{The American Chemical Society (ACS)}},
  series       = {{Journal of Medicinal Chemistry}},
  title        = {{Discovery and Optimization of the First Highly Effective and Orally Available Galectin-3 Inhibitors for Treatment of Fibrotic Disease}},
  url          = {{http://dx.doi.org/10.1021/acs.jmedchem.2c00660}},
  doi          = {{10.1021/acs.jmedchem.2c00660}},
  volume       = {{65}},
  year         = {{2022}},
}