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Papers by Mathias Färnegårdh

Current Medicinal Chemistry, Sep 1, 2009

Mini-reviews in Medicinal Chemistry, 2007

The following versions of software and data (see references i ○) were used in the production of t... more The following versions of software and data (see references i ○) were used in the production of this report:

Biochemical and Biophysical Research Communications

The following experimental techniques were used to determine the structure: X-RAY DIFFRACTION The... more The following experimental techniques were used to determine the structure: X-RAY DIFFRACTION The reported resolution of this entry is 2.20 Å. Percentile scores (ranging between 0-100) for global validation metrics of the entry are shown in the following graphic. The table shows the number of entries on which the scores are based. Metric Whole archive (#Entries) Similar resolution (#Entries, resolution range(Å)) R f ree 111664 4343 (2.20-2.20) Clashscore 122126 5027 (2.20-2.20) Ramachandran outliers 120053 4952 (2.20-2.20) Sidechain outliers 120020 4953 (2.20-2.20) RSRZ outliers 108989 4245 (2.20-2.20

Journal of Medicinal Chemistry, 2008

Journal of Medicinal Chemistry, 2006

A structure-based approach was used to optimize our new class of quinoline LXR modulators leading... more A structure-based approach was used to optimize our new class of quinoline LXR modulators leading to phenyl acetic acid substituted quinolines 15 and 16. Both compounds displayed good binding affinity for LXR and LXRR and were potent activators in LBD transactivation assays. The compounds also increased expression of ABCA1 and stimulated cholesterol efflux in THP-1 cells. Quinoline 16 showed good oral bioavailability and in vivo efficacy in a LDLr knockout mouse model for lesions.

Current Medicinal Chemistry, 2009

Bioorganic & Medicinal Chemistry, 2009

A series of 4-(amido-biarylether)-quinolines was prepared as potential LXR agonists. Appropriate ... more A series of 4-(amido-biarylether)-quinolines was prepared as potential LXR agonists. Appropriate substitution with amide groups provided high affinity LXR ligands, some with excellent potency and efficacy in functional assays of LXR activity. Novel amide 4g had a binding IC(50)=1.9 nM for LXRbeta and EC(50)=34 nM (96% efficacy relative to T0901317) in an ABCA1 gene expression assay in mouse J774 cells, demonstrating that 4-(biarylether)-quinolines with appropriate amide substitution are potent LXR agonists.

Mini-Reviews in Medicinal Chemistry, 2007

Bioorganic & Medicinal Chemistry Letters, 2006

Based on the examination of the crystal structure of rat TRbeta complexed with 3,5,3&... more Based on the examination of the crystal structure of rat TRbeta complexed with 3,5,3'-triiodo-l-thyronine (2) a novel TRbeta-selective indole derivative 6b was prepared and tested in vitro. This compound was found to be 14 times selective for TRbeta over TRalpha in binding and its beta-selectivity could be rationalized through the comparison of the X-ray crystallographic structures of 6b complexed with TRalpha and TRbeta.

Acta Crystallographica Section A Foundations of Crystallography, 2002

Nuclear receptors bind to DNA and activate in general the transcription of sets of genes in respo... more Nuclear receptors bind to DNA and activate in general the transcription of sets of genes in response to the binding of cognate ligands, usually small lipophilic molecules such as steroids, vitamins, and fatty acid derivatives. About 50 nuclear receptor genes have been identified in the human genome, but most of them have no known ligand and are therefore called orphans; their biological functions are also poorly understood. Among the orphan nuclear receptors, some appear to be constitutively active. We have solved the structure of the ligand-binding domain (LBD) of two such receptors: RORβ and ERR3. The human RORβ LBD was found in the transcriptionally active conformation thanks to the combined action of stearate, a fortuitous ligand, and a coactivator peptide. Mutagenesis based on the structure showed that RORβ transcriptional activity is in fact ligand-dependent, and thus RORβ constitutive activity is only apparent. The human ERR3 LBD in complex with a coactivator peptide was also found in the transcriptionally active conformation, but this time in the absence of any ligand, suggesting that ERR3 is indeed constitutively active. References: 1

Journal of Medicinal Chemistry, 2004

Hepatic blockade of glucocorticoid receptors (GR) suppresses glucose production and thus decrease... more Hepatic blockade of glucocorticoid receptors (GR) suppresses glucose production and thus decreases circulating glucose levels, but systemic glucocorticoid antagonism can produce adrenal insufficiency and other undesirable side effects. These hepatic and systemic responses might be dissected, leading to liver-selective pharmacology, when a GR antagonist is linked to a bile acid in an appropriate manner. Bile acid conjugation can be accomplished with a minimal loss of binding affinity for GR. The resultant conjugates remain potent in cell-based functional assays. A novel in vivo assay has been developed to simultaneously evaluate both hepatic and systemic GR blockade; this assay has been used to optimize the nature and site of the linker functionality, as well as the choice of the GR antagonist and the bile acid. This optimization led to the identification of A-348441, which reduces glucose levels and improves lipid profiles in an animal model of diabetes.

A new high-affinity thyroid hormone antagonist 6 with druglike properties was designed and synthe... more A new high-affinity thyroid hormone antagonist 6 with druglike properties was designed and synthesized. The compound behaved as an antagonist in a cell transactivation assay, and in a first in vivo experiment in rats.

SHP (short heterodimer partner) is an unusual orphan nuclear receptor consisting only of a ligand... more SHP (short heterodimer partner) is an unusual orphan nuclear receptor consisting only of a ligand-binding domain, and it exhibits unique features of interaction with conventional nuclear receptors. While the mechanistic basis of these interactions has remained enigmatic, SHP has been suggested to inhibit nuclear receptor activation by at least three alternatives; inhibition of DNA binding via dimerization, direct antagonism of coactivator function via competition, and possibly transrepression via recruitment of putative corepressors. We now show that SHP binds directly to estrogen receptors via LXXLL-related motifs. Similar motifs, referred to as NR (nuclear receptor) boxes, are usually critical for the binding of coactivators to the ligand-regulated activation domain AF-2 within nuclear receptors. In concordance with the NR box dependency, SHP requires the intact AF-2 domain of agonist-bound estrogen receptors for interaction. Mutations within the ligand-binding domain helix 12, or...

Current Medicinal Chemistry, Sep 1, 2009

Mini-reviews in Medicinal Chemistry, 2007

The following versions of software and data (see references i ○) were used in the production of t... more The following versions of software and data (see references i ○) were used in the production of this report:

Biochemical and Biophysical Research Communications

The following experimental techniques were used to determine the structure: X-RAY DIFFRACTION The... more The following experimental techniques were used to determine the structure: X-RAY DIFFRACTION The reported resolution of this entry is 2.20 Å. Percentile scores (ranging between 0-100) for global validation metrics of the entry are shown in the following graphic. The table shows the number of entries on which the scores are based. Metric Whole archive (#Entries) Similar resolution (#Entries, resolution range(Å)) R f ree 111664 4343 (2.20-2.20) Clashscore 122126 5027 (2.20-2.20) Ramachandran outliers 120053 4952 (2.20-2.20) Sidechain outliers 120020 4953 (2.20-2.20) RSRZ outliers 108989 4245 (2.20-2.20

Journal of Medicinal Chemistry, 2008

Journal of Medicinal Chemistry, 2006

A structure-based approach was used to optimize our new class of quinoline LXR modulators leading... more A structure-based approach was used to optimize our new class of quinoline LXR modulators leading to phenyl acetic acid substituted quinolines 15 and 16. Both compounds displayed good binding affinity for LXR and LXRR and were potent activators in LBD transactivation assays. The compounds also increased expression of ABCA1 and stimulated cholesterol efflux in THP-1 cells. Quinoline 16 showed good oral bioavailability and in vivo efficacy in a LDLr knockout mouse model for lesions.

Current Medicinal Chemistry, 2009

Bioorganic & Medicinal Chemistry, 2009

A series of 4-(amido-biarylether)-quinolines was prepared as potential LXR agonists. Appropriate ... more A series of 4-(amido-biarylether)-quinolines was prepared as potential LXR agonists. Appropriate substitution with amide groups provided high affinity LXR ligands, some with excellent potency and efficacy in functional assays of LXR activity. Novel amide 4g had a binding IC(50)=1.9 nM for LXRbeta and EC(50)=34 nM (96% efficacy relative to T0901317) in an ABCA1 gene expression assay in mouse J774 cells, demonstrating that 4-(biarylether)-quinolines with appropriate amide substitution are potent LXR agonists.

Mini-Reviews in Medicinal Chemistry, 2007

Bioorganic & Medicinal Chemistry Letters, 2006

Based on the examination of the crystal structure of rat TRbeta complexed with 3,5,3&... more Based on the examination of the crystal structure of rat TRbeta complexed with 3,5,3'-triiodo-l-thyronine (2) a novel TRbeta-selective indole derivative 6b was prepared and tested in vitro. This compound was found to be 14 times selective for TRbeta over TRalpha in binding and its beta-selectivity could be rationalized through the comparison of the X-ray crystallographic structures of 6b complexed with TRalpha and TRbeta.

Acta Crystallographica Section A Foundations of Crystallography, 2002

Nuclear receptors bind to DNA and activate in general the transcription of sets of genes in respo... more Nuclear receptors bind to DNA and activate in general the transcription of sets of genes in response to the binding of cognate ligands, usually small lipophilic molecules such as steroids, vitamins, and fatty acid derivatives. About 50 nuclear receptor genes have been identified in the human genome, but most of them have no known ligand and are therefore called orphans; their biological functions are also poorly understood. Among the orphan nuclear receptors, some appear to be constitutively active. We have solved the structure of the ligand-binding domain (LBD) of two such receptors: RORβ and ERR3. The human RORβ LBD was found in the transcriptionally active conformation thanks to the combined action of stearate, a fortuitous ligand, and a coactivator peptide. Mutagenesis based on the structure showed that RORβ transcriptional activity is in fact ligand-dependent, and thus RORβ constitutive activity is only apparent. The human ERR3 LBD in complex with a coactivator peptide was also found in the transcriptionally active conformation, but this time in the absence of any ligand, suggesting that ERR3 is indeed constitutively active. References: 1

Journal of Medicinal Chemistry, 2004

Hepatic blockade of glucocorticoid receptors (GR) suppresses glucose production and thus decrease... more Hepatic blockade of glucocorticoid receptors (GR) suppresses glucose production and thus decreases circulating glucose levels, but systemic glucocorticoid antagonism can produce adrenal insufficiency and other undesirable side effects. These hepatic and systemic responses might be dissected, leading to liver-selective pharmacology, when a GR antagonist is linked to a bile acid in an appropriate manner. Bile acid conjugation can be accomplished with a minimal loss of binding affinity for GR. The resultant conjugates remain potent in cell-based functional assays. A novel in vivo assay has been developed to simultaneously evaluate both hepatic and systemic GR blockade; this assay has been used to optimize the nature and site of the linker functionality, as well as the choice of the GR antagonist and the bile acid. This optimization led to the identification of A-348441, which reduces glucose levels and improves lipid profiles in an animal model of diabetes.

A new high-affinity thyroid hormone antagonist 6 with druglike properties was designed and synthe... more A new high-affinity thyroid hormone antagonist 6 with druglike properties was designed and synthesized. The compound behaved as an antagonist in a cell transactivation assay, and in a first in vivo experiment in rats.

SHP (short heterodimer partner) is an unusual orphan nuclear receptor consisting only of a ligand... more SHP (short heterodimer partner) is an unusual orphan nuclear receptor consisting only of a ligand-binding domain, and it exhibits unique features of interaction with conventional nuclear receptors. While the mechanistic basis of these interactions has remained enigmatic, SHP has been suggested to inhibit nuclear receptor activation by at least three alternatives; inhibition of DNA binding via dimerization, direct antagonism of coactivator function via competition, and possibly transrepression via recruitment of putative corepressors. We now show that SHP binds directly to estrogen receptors via LXXLL-related motifs. Similar motifs, referred to as NR (nuclear receptor) boxes, are usually critical for the binding of coactivators to the ligand-regulated activation domain AF-2 within nuclear receptors. In concordance with the NR box dependency, SHP requires the intact AF-2 domain of agonist-bound estrogen receptors for interaction. Mutations within the ligand-binding domain helix 12, or...