Discovery of Selective and Orally Available Galectin-1 Inhibitors
(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
- 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
- organization
- publishing date
- 2023-12-07
- 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
- 2024-08-07 19:19:19
@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% > 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}}, }