Isochromanone-based urotensin-II receptor agonists
Lehmann, Fredrik ; Currier, Erika A. ; Olsson, Roger LU
; Hacksell, Uli
and Luthman, Kristina
(2005)
In Bioorganic and Medicinal Chemistry
13(8).
p.3057-3068
- Abstract
A series of analogues of the selective non-peptide urotensin II (UII) receptor agonist 3-(4-chlorophenyl)-3-(2-dimethylaminoethyl)-isochroman-1-one (AC-7954, 1) was synthesized and evaluated for UII agonist activity using a functional cell-based assay. The introduction of a methyl group in the 4-position resulted in a complete loss of activity, whereas substituents in the aromatic rings were beneficial. Sterically demanding amino groups were also detrimental to the activity. Several potent agonists were identified, six compounds being equally or more potent than 1. The most potent compound in the series was the 6,7-dimethyl analogue of 1 (16, pEC50 6.87). The racemate of 16 was resolved into the pure enantiomers using... (More)
A series of analogues of the selective non-peptide urotensin II (UII) receptor agonist 3-(4-chlorophenyl)-3-(2-dimethylaminoethyl)-isochroman-1-one (AC-7954, 1) was synthesized and evaluated for UII agonist activity using a functional cell-based assay. The introduction of a methyl group in the 4-position resulted in a complete loss of activity, whereas substituents in the aromatic rings were beneficial. Sterically demanding amino groups were also detrimental to the activity. Several potent agonists were identified, six compounds being equally or more potent than 1. The most potent compound in the series was the 6,7-dimethyl analogue of 1 (16, pEC50 6.87). The racemate of 16 was resolved into the pure enantiomers using preparative straight phase HPLC. It was shown that the potency resides in the (+)-enantiomer (pEC50 7.11). The synthesized compounds seem to be selective for the UII receptor as no activities were observed at the closely related SSTR3 and 5 receptors.
(Less)
- author
- Lehmann, Fredrik
; Currier, Erika A.
; Olsson, Roger
LU
; Hacksell, Uli
and Luthman, Kristina
- publishing date
- 2005-04-15
- type
- Contribution to journal
- publication status
- published
- in
- Bioorganic and Medicinal Chemistry
- volume
- 13
- issue
- 8
- pages
- 12 pages
- publisher
- Elsevier
- external identifiers
-
- scopus:15244344609
- pmid:15781415
- ISSN
- 0968-0896
- DOI
- 10.1016/j.bmc.2005.01.056
- language
- English
- LU publication?
- no
- id
- a500e798-48e1-4819-8b69-3529b9735e86
- date added to LUP
- 2019-10-02 10:34:46
- date last changed
- 2024-04-02 17:35:22
@article{a500e798-48e1-4819-8b69-3529b9735e86,
abstract = {{<p>A series of analogues of the selective non-peptide urotensin II (UII) receptor agonist 3-(4-chlorophenyl)-3-(2-dimethylaminoethyl)-isochroman-1-one (AC-7954, 1) was synthesized and evaluated for UII agonist activity using a functional cell-based assay. The introduction of a methyl group in the 4-position resulted in a complete loss of activity, whereas substituents in the aromatic rings were beneficial. Sterically demanding amino groups were also detrimental to the activity. Several potent agonists were identified, six compounds being equally or more potent than 1. The most potent compound in the series was the 6,7-dimethyl analogue of 1 (16, pEC<sub>50</sub> 6.87). The racemate of 16 was resolved into the pure enantiomers using preparative straight phase HPLC. It was shown that the potency resides in the (+)-enantiomer (pEC<sub>50</sub> 7.11). The synthesized compounds seem to be selective for the UII receptor as no activities were observed at the closely related SSTR3 and 5 receptors.</p>}},
author = {{Lehmann, Fredrik and Currier, Erika A. and Olsson, Roger and Hacksell, Uli and Luthman, Kristina}},
issn = {{0968-0896}},
language = {{eng}},
month = {{04}},
number = {{8}},
pages = {{3057--3068}},
publisher = {{Elsevier}},
series = {{Bioorganic and Medicinal Chemistry}},
title = {{Isochromanone-based urotensin-II receptor agonists}},
url = {{http://dx.doi.org/10.1016/j.bmc.2005.01.056}},
doi = {{10.1016/j.bmc.2005.01.056}},
volume = {{13}},
year = {{2005}},
}