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Discovery of Selective and Orally Available Galectin-1 Inhibitors

Zetterberg, Fredrik R ; Diehl, Carl LU ; Håkansson, Maria LU ; Kahl-Knutson, Barbro LU ; Leffler, Hakon LU ; Nilsson, Ulf J LU ; Peterson, Kristoffer LU ; Roper, James A and Slack, Robert J (2023) In Journal of Medicinal Chemistry 66(24). p.16980-16990
Abstract

A new series of orally available α-d-galactopyranosides with high affinity and specificity toward galectin-1 have been discovered. High affinity and specificity were achieved by changing six-membered aryl-triazolyl substituents in a series of recently published galectin-3-selective α-d-thiogalactosides (e.g., GB1107 Kd galectin-1/3 3.7/0.037 μM) for five-membered heterocycles such as thiazoles. The in vitro pharmacokinetic properties were optimized, resulting in several galectin-1 inhibitors with favorable properties. One compound, GB1490 (Kd galectin-1/3 0.4/2.7 μM), was selected for further characterization toward a panel of galectins showing a selectivity of 6- to 320-fold dependent on galectin. The X-ray... (More)

A new series of orally available α-d-galactopyranosides with high affinity and specificity toward galectin-1 have been discovered. High affinity and specificity were achieved by changing six-membered aryl-triazolyl substituents in a series of recently published galectin-3-selective α-d-thiogalactosides (e.g., GB1107 Kd galectin-1/3 3.7/0.037 μM) for five-membered heterocycles such as thiazoles. The in vitro pharmacokinetic properties were optimized, resulting in several galectin-1 inhibitors with favorable properties. One compound, GB1490 (Kd galectin-1/3 0.4/2.7 μM), was selected for further characterization toward a panel of galectins showing a selectivity of 6- to 320-fold dependent on galectin. The X-ray structure of GB1490 bound to galectin-1 reveals the compound bound in a single conformation in the carbohydrate binding site. GB1490 was shown to reverse galectin-1-induced apoptosis of Jurkat cells at low μM concentrations. No cell cytotoxicity was observed for GB1490 up to 90 μM in the A549 cells. In pharmacokinetic studies in mice, GB1490 showed high oral bioavailability (F% > 99%).

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author
; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Medicinal Chemistry
volume
66
issue
24
pages
16980 - 16990
publisher
The American Chemical Society (ACS)
external identifiers
  • scopus:85180116081
  • pmid:38059452
  • pmid:38059452
ISSN
1520-4804
DOI
10.1021/acs.jmedchem.3c01787
language
English
LU publication?
yes
id
302a24c6-d2be-4e16-bace-54aa1ea232cf
date added to LUP
2023-12-14 11:37:28
date last changed
2024-04-17 09:51:46
@article{302a24c6-d2be-4e16-bace-54aa1ea232cf,
  abstract     = {{<p>A new series of orally available α-d-galactopyranosides with high affinity and specificity toward galectin-1 have been discovered. High affinity and specificity were achieved by changing six-membered aryl-triazolyl substituents in a series of recently published galectin-3-selective α-d-thiogalactosides (e.g., GB1107 K<sub>d</sub> galectin-1/3 3.7/0.037 μM) for five-membered heterocycles such as thiazoles. The in vitro pharmacokinetic properties were optimized, resulting in several galectin-1 inhibitors with favorable properties. One compound, GB1490 (K<sub>d</sub> galectin-1/3 0.4/2.7 μM), was selected for further characterization toward a panel of galectins showing a selectivity of 6- to 320-fold dependent on galectin. The X-ray structure of GB1490 bound to galectin-1 reveals the compound bound in a single conformation in the carbohydrate binding site. GB1490 was shown to reverse galectin-1-induced apoptosis of Jurkat cells at low μM concentrations. No cell cytotoxicity was observed for GB1490 up to 90 μM in the A549 cells. In pharmacokinetic studies in mice, GB1490 showed high oral bioavailability (F% &gt; 99%).</p>}},
  author       = {{Zetterberg, Fredrik R and Diehl, Carl and Håkansson, Maria and Kahl-Knutson, Barbro and Leffler, Hakon and Nilsson, Ulf J and Peterson, Kristoffer and Roper, James A and Slack, Robert J}},
  issn         = {{1520-4804}},
  language     = {{eng}},
  month        = {{12}},
  number       = {{24}},
  pages        = {{16980--16990}},
  publisher    = {{The American Chemical Society (ACS)}},
  series       = {{Journal of Medicinal Chemistry}},
  title        = {{Discovery of Selective and Orally Available Galectin-1 Inhibitors}},
  url          = {{http://dx.doi.org/10.1021/acs.jmedchem.3c01787}},
  doi          = {{10.1021/acs.jmedchem.3c01787}},
  volume       = {{66}},
  year         = {{2023}},
}