| 1. |
- Sundén, Henrik, 1978, et al.
(författare)
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Synthesis and Biological Evaluation of Second-Generation Tropanol-Based Androgen Receptor Modulators
- 2015
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 1520-4804 .- 0022-2623. ; 58:3, s. 1569-1574
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Tidskriftsartikel (refereegranskat)abstract
- To circumvent antiandrogen resistance in prostate cancer, antiandrogens effective for both the androgen receptor (AR) and AR mutants are required. The AR antagonists in this study originate from previous findings, which showed that subtle differences in substitution pattern lead to a conformational change that alters the ligand activity, rendering an agonist to an antagonist. We have identified small yet potent tropanol-based ligands possessing significant antiandrogenic activity with both wild-type AR and the two most common AR ligand binding domain (LBD) mutants.
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| 2. |
- Sundén, Henrik, 1978, et al.
(författare)
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Chiral Dihydrobenzofuran Acids Show Potent Retinoid X Receptor-Nuclear Receptor Related 1 Protein Dimer Activation
- 2016
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 59:3, s. 1232-1238
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Tidskriftsartikel (refereegranskat)abstract
- The nuclear receptor Nurr1 can be activated by RXR via heterodimerization (RXR-Nurr1) and is a promising target for treating neurodegenerative diseases. We herein report the enantioselective synthesis and SAR of sterically constricted benzofurans at RXR. The established SAR, using whole cell functional assays, lead to the full agonist 9a at RXR (pEC50 of 8.2) and RXR-Nurr1. The X-ray structure shows enantiomeric discrimination where 9a optimally addresses the ligand binding pocket of RXR.
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| 3. |
- Lehmann, Fredrik, 1976, et al.
(författare)
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Design, parallel synthesis and SAR of novel urotensin II receptor agonists
- 2007
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Ingår i: European Journal of Medicinal Chemistry. - : Elsevier BV. - 0223-5234 .- 1768-3254. ; 42, s. 276-285
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Tidskriftsartikel (refereegranskat)abstract
- A 30-membered library of amides based on the potent urotensin II (UII) receptor agonist FL104, has been synthesized from ten different carboxylic acids and three amines. A synthetic protocol producing the amides in 47-98% yield has been developed in which the purification involved only extractions and in a few cases filtration through an ion-exchange resin. It was found that 5 mg of starting material was enough to obtain reproducible results and excellent purities. Thus, the procedure is estimated to be transferable to fully automated systems. The synthesized compounds were evaluated for their UII receptor agonistic activities using a cell-based assay (R-SAT). The most active compounds were the 4-trifluoromethylcinnamic amides of 1-(4-chlorophenyl)-3-dimethylamino-propylamine and 1-(2-naphthyl)-3-dimethylamino-propylamine, both showed EC50 values of 130 nM. © 2006 Elsevier Masson SAS. All rights reserved.
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| 4. |
- Lehmann, Fredrik, 1976, et al.
(författare)
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Novel potent and efficacious nonpeptidic urotensin II receptor agonists
- 2006
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 49, s. 2232-2240
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Tidskriftsartikel (refereegranskat)abstract
- Six different series of nonpeptidic urotensin II receptor agonists have been synthesized and evaluated for their agonistic activity in a cell-based assay (R-SAT). The compounds are ring-opened analogues of the isochromanone-based agonist AC-7954 with different functionalities constituting the linker between the two aromatic ring moieties. Several of the compounds are highly potent and efficacious, with N-[1-(4-chlorophenyl)-3-(dimethylamino)- propyl]-4-phenylbenzamide oxalate (5d) being the most potent. The pure enantiomers of 5d were obtained from the corresponding diastereomeric amides. It was shown by a combination of X-ray crystallography and chemical correlation that the activity resides in the S-enantiomer of 5d (pEC50 7.49). © 2006 American Chemical Society.
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| 5. |
- Schäfer, Anja, et al.
(författare)
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Bexarotene prodrugs: Targeting through cleavage by NQO1 (DT-diaphorase)
- 2014
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Ingår i: Bioorganic and Medicinal Chemistry Letters. - : Elsevier BV. - 0960-894X .- 1464-3405. ; 24:8, s. 1944-1947
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Tidskriftsartikel (refereegranskat)abstract
- Bexarotene, a retinoid X receptor (RXR) agonist, is being tested as a potential disease modifying treatment for neurodegenerative conditions. To limit the peripheral exposure of bexarotene and release it only in the affected areas of the brain, we designed a prodrug strategy based on the enzyme NAD(P)H/quinone oxidoreductase (NQO1) that is elevated in neurodegenerative diseases. A series of indolequinones (known substrates of NQO1) was synthesized and coupled to bexarotene. Bexarotene-3-(hydroxymethyl)-5-methoxy-1,2-dimethyl- 1H-indole-4,7-dione ester 7a was cleaved best by NQO1. The prodrugs are not cleaved by esterase. © 2014 Elsevier Ltd. All rights reserved.
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| 6. |
- Sauvée, Claire, et al.
(författare)
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The A-CD analogue of 16 beta,17 alpha-estriol is a potent and highly selective estrogen receptor beta agonist
- 2013
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Ingår i: Medchemcomm. - : Royal Society of Chemistry (RSC). - 2040-2503 .- 2040-2511. ; 4:11, s. 1439-1442
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Tidskriftsartikel (refereegranskat)abstract
- Selective estrogen receptor beta (ER beta) agonists display neuroprotective properties in animal models and hold promise in the treatment of neurodegenerative diseases. In our quest to design, synthesize and evaluate potent and safe ER beta agonists, we focused on making an analogue of 16 beta,17 alpha-estriol (16,17-epiestriol), a potent and one of the most ER beta selective endogenous estrogens reported. Herein we disclose the synthesis and in vitro evaluation of an analogue based on the recently introduced A-CD scaffold. A 14-step synthesis based on the Hajos-Parrish ketone resulted in the discovery of (1S,2S,3aS,5S,7aS)-5-(4-hydroxyphenyl)-7a-methyloctahydro-1H-indene-1,2- diol (15). This A-CD analogue of 16 beta, 17 alpha-estriol is a highly selective (500-fold) ER beta full agonist over ER alpha with a pEC(50) of 7.7 at ER beta. Molecular modelling suggests that 15 turns around in the ligand-binding domain compared to estriol, thus the 7a-methyl occupies the alpha-face, which might explain the high selectivity.
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| 7. |
- Lehmann, Fredrik, 1976, et al.
(författare)
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Isochromanone-based urotensin-II receptor agonists.
- 2005
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Ingår i: Bioorganic & medicinal chemistry. - : Elsevier BV. - 0968-0896. ; 13:8, s. 3057-68
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Tidskriftsartikel (refereegranskat)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 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.
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| 8. |
- Olsson, Roger, et al.
(författare)
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Chelation-controlled regioselective endo cleavage and stereoselective C-1 alkylation of pentofuranosides
- 1998
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Ingår i: Journal of the Chemical Society - Perkin Transactions 1. - : Royal Society of Chemistry (RSC). - 0300-922X .- 1364-5463. ; :4, s. 785-790
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Tidskriftsartikel (refereegranskat)abstract
- Combinations of Lewis acids and nucleophilic reagents trigger endo-opening of the furanoside ring of methyl furanosides 1, 10 and 13, resulting in the attachment of the nucleophilic group at C-1 of the carbohydrate. The stereoselectivity in the C-C bond-forming step is low for the 2-deoxyfuranosides but very high (dr 1:99) for the furanosides carrying a methoxy group in the 2-position when a combination of TiCl4 and Me2Zn is used. Different selectivities are obtained with Me2Zn as compared with Me3Al. Reagents based on several organometallic reagents of Al, Si, Ti and Zn in combination with TiCl4 can be used.
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| 9. |
- Olsson, Roger, et al.
(författare)
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Endocyclic cleavage of glycosides. VI. Substituent effects of the alkylative endocyclic cleavage of glycosides
- 1998
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Ingår i: Tetrahedron. - 0040-4020. ; 54:15, s. 3935-3954
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Tidskriftsartikel (refereegranskat)abstract
- A number of pentopyranoside derivatives were treated with Me 3 Al in order to investigate the influence of structural parameters on the methyl group transfer in the endocyclic alkylative cleavage reaction of these substrates. A cyclic CH ··· O hydrogen bonded model is suggested as an intermediate, which is used to explain the stereoselectivities for different substrates. In several, cases the diastereoselectivities were better than 9:1.
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| 10. |
- Olsson, Roger, et al.
(författare)
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Organotitanium-induced stereoselective alkylative endo-cleavage of benzyl pentopyranosides
- 1998
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Ingår i: Carbohydrate Research. - 0008-6215. ; 307:1-2, s. 13-18
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Tidskriftsartikel (refereegranskat)abstract
- The results presented are the first examples where organotitanium reagents induced alkylative endo-cleavage of carbohydrates. The best conditions for the alkylative transfer of a methyl group to benzyl 2-deoxy- 2-C-methyl-4-O-(tert-butyldimethylsilyl)-α-D-arabinopyranoside (1) were the application of one equivalent of AlMe3 followed by four equivalents of MeTiCl3 generated by mixing TiCl4 and ZnMe2 in a ratio 2:1, or, alternatively, treatment of I with two equivalents of 1:1 Me2TiCl2-ZnMe2. Both the yields and diastereoselectivities were comparable with those of the reaction with AlMe3 but the titanium reagents were more reactive and could be applied at much lower temperatures than the aluminium reagent.
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