Konrad Koehler - Academia.edu (original) (raw)
Papers by Konrad Koehler
Experimental and Molecular Therapeutics
![Research paper thumbnail of Discovery of 3-Cyano-N-(3-(1-isobutyrylpiperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide. A Potent, Selective, and Orally Bioavailable Retinoic Acid Receptor-Related Orphan Receptor C2 (RORC2) Inverse Agonist](https://attachments.academia-assets.com/70131258/thumbnails/1.jpg)
](Journal of medicinal chemistry, Jan 21, 2018
The nuclear hormone receptor RORC2 (also known as RORγt) is a promising target for the treatment ... more The nuclear hormone receptor RORC2 (also known as RORγt) is a promising target for the treatment of autoimmune diseases. A small molecule, inverse agonist of the receptor is anticipated to reduce production of IL-17, a key pro-inflammatory cytokine. Through a high-throughput screening approach, we identified a molecule displaying promising binding affinity for RORC2, inhibition of IL-17 production in Th17 cells, and selectivity against the related RORA and RORB receptor isoforms. Lead optimization to improve the potency and metabolic stability of this hit focused on two key design strategies, namely, iterative optimization driven by increasing lipophilic efficiency and structure-guided conformational restriction to achieve optimal ground state energetics and maximize receptor residence time. This approach successfully identified 3-cyano-N-(3-(1-isobutyrylpiperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide as a potent and selective RORC2 inverse agoni...
ChemInform
ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance t... more ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Bulletin des Sociétés Chimiques Belges, 1983
A new method for the preparation of p-lactams has been developed. The protocol involves 1,3-dipol... more A new method for the preparation of p-lactams has been developed. The protocol involves 1,3-dipolar cycloaddition of nitrones with nitro substituted alkenes followed by a subsequent reorganization of the resulting 5-nitroisoxazolidine isomer. The utilization of a-silyl substituted amines as azomethine ylide equivalents has also been explored.
Antiviral chemistry & chemotherapy, 2003
Hepatitis C virus (HCV) is a highly prevalent virus and one of the major agents of chronic hepati... more Hepatitis C virus (HCV) is a highly prevalent virus and one of the major agents of chronic hepatitis. Since HCV NS3 protease is essential for the processing of HCV polyprotein, this protease is a target of choice to control HCV replication. Peptide inhibitors of NS3 were developed by selective amino acid replacement of six leader sequences, corresponding to regions of HCV polyprotein that are cleaved by NS3. The large numbers of potential 14-mer and 16-mer peptide inhibitors thus obtained were tested against NS3 using the fluorescent probe RETS1 and peptide cofactor SVVIVGRIILSGRA from NS4A protein. This afforded several peptide inhibitors with an IC50 of around 2 microM. These peptides may be good leading compounds for the development of peptidomimetics to control HCV replication in the treatment of chronic hepatitis C.
Drug design and discovery, 1995
A unified pharmacophore model of the benzodiazepine receptor (BzR) has been developed using the t... more A unified pharmacophore model of the benzodiazepine receptor (BzR) has been developed using the techniques of chemical synthesis, radioligand binding, and receptor mapping. This model is based on 136 different ligands spanning ten structurally diverse classes of compounds and qualitatively accounts for the relative affinities, efficacies, and functional effects (agonism vs. antagonism vs. inverse agonism) displayed by various ligands at the BzR. In addition, the model is expanded to account for the pharmacology of a recently discovered BzR receptor subtype termed the 'Diazepam-Insensitive' (DI) BzR. Moreover, the unified model described here is compared and contrasted with other published pharmacophore models. As previously reported, the synthesis of both partial agonists and partial inverse agonists has been achieved by using parts of this model. Partial agonists are of interest as potentially improved agents for treatment of anxiety disorders, while the partial inverse ago...
Encyclopedia of Hormones, 2003
Journal of Medicinal Chemistry, 1992
... Allen,+ Anthony J. LaLoggia,t Linda J. Darn,' Michael J. Martin,t Gabriele C... more ... Allen,+ Anthony J. LaLoggia,t Linda J. Darn,' Michael J. Martin,t Gabriele Costantino,$ Timothy J. Hagen,g Konrad F. Koehler,'J Phil Skolnick,* and ... equation will improve the fit to a training set of data, but inclusion of too many variables will often cause a sub-stantial reduction in ...
Proceedings of the National Academy of Sciences, 1986
The diterpene diester phorbol 12-myristate 13-acetate and the alkaloid teleocidin B are structura... more The diterpene diester phorbol 12-myristate 13-acetate and the alkaloid teleocidin B are structurally unrelated natural products that display similar potent irritant and tumor-promoting activities. Computer modeling of these and other structural classes of tumor promoters show a marked similarity in the relative positions of certain heteroatoms and hydrophobic groups. For phorbol this mapping consists of the C-4, C-9, and C-20 hydroxyl groups as well as a hydrophobic region frled by a long-chain acyl functionality attached to either the C-12 or the C-13 positions. Diacylglycerols, thought to be the endogenous activators of the major phorbol ester receptor protein kinase C likewise fit this model in a stereospecific fashion. As an initial test of the utility of the model, members of a new and simplified class of activators were synthesized that possess the predicted essential structural features. These compounds all inhibited specific phorbol ester binding to protein kinase C, albeit with low affinity (10-60 ,.M); further analysis of one derivative, decylhydroxylindole, confirmed that the inhibition of phorbol ester binding was competitive. This same derivative inhibited epidermal growth factor binding in intact Swiss 3T3 cells and studies with another derivative showed phosphorylation of a 40-kDa protein in platelets. Both of these in vivo responses are characteristic of phorbol esters.
Proceedings of the National Academy of Sciences, 1988
The bryostatins are macrocyclic lactones that represent an additional structural class of potent ... more The bryostatins are macrocyclic lactones that represent an additional structural class of potent activators of protein kinase C. These marine animal biosynthetic products are of unusual interest because they induce only a subset of the biological responses induced by the phorbol esters. We have now determined the binding affinities of naturally occurring and semisynthetic bryostatins for protein kinase C by competition analysis with [26-3Hlbryostatin 4 as the radioactive ligand. Esterification of the hydroxyl group at C26 caused dramatic loss of activity as did inversion of the asymmetric center at this position. In contrast, neither of the ester groups at C7 and C20 had a major influence on activity. Computer modeling of the phorbol esters, related diterpenes, and indole alkaloids suggested that the C20, C9, and C4 oxygens of phorbol represented critical elements of the phorbol ester pharmacophore. The C26 oxygen of the bryostatins, together with the C1 and C19 oxygens, gave an excellent spatial correlation with this model, with a root-mean-square deviation of 0.16 A (compared to 0.10-0.35 A among phorbol-related
Nature Reviews Drug Discovery, 2011
The two oestrogen receptor subtypes α and β are hormone-regulated modulators of intracellular sig... more The two oestrogen receptor subtypes α and β are hormone-regulated modulators of intracellular signalling and gene expression. Regulation of oestrogen receptor activity is crucial not only for development and homeostasis but also for the treatment of various diseases and symptoms. Classical selective oestrogen receptor modulators are well established in the treatment of breast cancer and osteoporosis, but emerging data suggest that the development of subtype-selective ligands that specifically target either oestrogen receptor-α or oestrogen receptor-β could be a more optimal approach for the treatment of cancer, cardiovascular disease, multiple sclerosis and Alzheimer's disease.
Molecular Endocrinology, 2005
Two-point mutations in the human glucocorticoid receptor have been studied by computer simulation... more Two-point mutations in the human glucocorticoid receptor have been studied by computer simulations to rationalize experimental data, where mutants comprising the V571M substitution improve both transcriptional activity and affinity for aldosterone despite large distances between the mutated residue and the coactivator-binding surface and ligand-binding pocket, respectively. Our molecular dynamics simulations show that the V571M mutation modifies the coactivator-binding site defined by helices 3, 4, and 12, and that specific structural rearrangement of the coactivator-binding site correlates well with transactivation data. A similar reorganization of the coactivator-binding cleft is observed in crystallographic structures of the estrogen receptor in the presence of coactiva-tor peptide, compared with structures without peptide, indicating that induced fit for coactivator binding is a general phenomenon for nuclear receptors. These results suggest that the V571M substitution facilitates recruitment of coactivator protein by promotion of a conformational substate reducing the energetic penalty for the induced fit of the receptor-coactivator complex. Furthermore, our simulations of V571M mutants showed reduced fluctuations of residues lining the ligandbinding pocket. This indicates that a reduction of the entropic cost for ligand binding may explain the increased affinity of V571M mutants for certain ligands. (Molecular Endocrinology 19: 1960-1977, 2005) N UCLEAR RECEPTORS are ligand-activated transcription factors that regulate the expression of target genes in a cell-and promoter-specific manner. Key to nuclear receptor activation by agonist ligands is positioning of the C-terminal ␣-helix [helix 12 H12)]) of the ligand-binding domain (LBD) in a conformation that promotes and prevents binding of coactivator and corepressor proteins, respectively (1). The glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) are homologous members of the steroid hormone receptor superfamily. Intriguingly, whereas the GR interacts primarily with glucocorticoid ligands, the MR is activated by both glucocorticoids and mineralocorticoids. Synthetic glucocorticoids are widely used in treatment of inflammatory and immune disorders, such as asthma, and mineralocorticoids are involved in regulation of the electrolytic balance, affecting renal function and blood pressure among others.
Life Sciences, 1991
In order to employ rational drug design in the discovery of selective benzodiazepine receptor ago... more In order to employ rational drug design in the discovery of selective benzodiazepine receptor agonists and inverse agonists, pharmacophore/receptor models for both these activities must first be established. Recently, a pharmacophore for the inverse agonist site has been formulated employing the most recent receptor mapping techniques (22). The continuation of this approach to the pharmacophore for agonist ligands has permitted a definition of this site independently of the inverse agonist model. The agonist pharmacophore/receptor contains two hydrogen bond donating sites of interaction (H1 and H2) located about 6.5 A from each other, as well as three areas of lipophilic interaction (L1-L3). The areas L1 and L2 are critical for agonist activity; moreover, some ligands also require an interaction in a third lipophilic area termed L3. This is in agreement with previous work (12-23). In addition, an area of negative steric interaction (S1) between the ligand and receptor-binding protein is defined. In regard to the pharmacophore, it was established that the alignment rule for agonist beta-carbolines is different from that which elicits inverse agonist activity. Consideration of the pharmacophore has resulted in the synthesis of a new beta-carboline 16 which elicits agonist activity. This ligand 16 not only satisfied the requirements of the pharmacophore, but more importantly it elicited both anticonvulsant and anxiolytic activity, but was devoid of the myorelaxant/ataxic properties associated with the benzodiazepines.
Journal of the American Chemical Society, 1981
The Journal of Organic Chemistry, 1987
... (26) Chan, TH; Fleming, I. Synthesis 1979, 761. (27) Padwa, A.; Carter, S. P.; Chiacchio, U.;... more ... (26) Chan, TH; Fleming, I. Synthesis 1979, 761. (27) Padwa, A.; Carter, S. P.; Chiacchio, U.; Kline, D. N. Tetrahedron Lett. ... (34) Ali, S. A.; Senaratne, PA; Illig, C. R.; Meckler, H.; Tufariello, (35) Padwa, A.; Fisera, L.; Koehler, KF; Rodriguez, A,; Wong, GK JJ Tetrahedron Lett. ...
The Journal of Organic Chemistry, 1984
Crystallographic Data a n d X-ray Structure Analysis of 13a. Crystals of 13a are triclinic, space... more Crystallographic Data a n d X-ray Structure Analysis of 13a. Crystals of 13a are triclinic, space group Pi: a = 10.91 (1) b = 9.570 (3), c = 8.758 (8) A; a = 65.15 (l), @ = 66.94 (31, y = 71.24 (1)O; 2 = 2; d, = 1.21 g ~m-~. Intensities were measured by using Mo Ka radiation [Philips PWllOO diffractometer, graphite monochromator, 8-28 scan mode, 3 < 8 < 25O, scan speed 0.025O s-', scan width deg 1.7 + 0.6 tan 81. The total number of independent reflexions measured was 2384. The structure was solved by direct methods3' and refined by full-matrix least-squares3, to a final R-factor of 4.8%. In the refinements 1934 reflections with intensities greater than the standard deviation from counting statistics were used. Hydrogen atoms were found from difference Fourier syntheses. In the last cycles 263 parameters were refined (scale factor, extinction parameter, positional
The Journal of Organic Chemistry, 1984
Journal of Medicinal Chemistry, 1993
Several 1,4-diazepines were recently reported to bind with high affinities to the "diaze... more Several 1,4-diazepines were recently reported to bind with high affinities to the "diazepam-insensitive" (DI) isoform of the benzodiazepine receptor (BzR) (Korpi, E.R.; Uusi-Oukari, M.; Wegelius, K. Eur. J. Pharm. 1992, 213, 323-329. Wong, G.; Skolnick, P. Eur. J. Pharmacol. Mol. Pharm. Sec. 1992, 225, 63-68). However, only the putative ethanol antagonist 1 (Ro 15-4513) displayed modest selectivity for the DI site compared to other "diazepam-sensitive" (DS) BzR isoforms. In order to probe the requirements for selective, high-affinity binding to the DI site, the affinities of 47 benzodiazepines have been determined at both DI and DS BzR sites. In addition, single X-ray crystallographic analyses for three of these derivatives, 5 (Ro 17-1812), 6 (Ro 16-6028), and 42 (Ro 14-5974), are reported. The radioligand binding studies reveal that modifications to the 3-, 7-, and 8-positions of 6-oxoimidazo[1,5-alpha] [1,4]benzodiazepines have a marked influence on the Ki(DI)/Ki(DS) ratios. In order to more precisely determine the structural requirements for both high affinity and selectivity at DI BzR relative to DS, 3D-QSAR analyses were carried out on ligand affinities at both of these BzR isoforms. This analysis was based, in part, on the new X-ray crystallographic data. Satisfactory cross-validated regression equations were obtained individually for the logarithms of ligand affinities at DI and DS as well as for the differences of the logarithms of their affinities at these two isoforms (cross-validated R2 > 0.70 for all three regression equations). The steric and electrostatic 3D-QSAR DI and DS maps are in qualitative accord with the structure-activity relationship (SAR) data. Furthermore, the DI and DI/DS maps may be useful in the design of ligands with enhanced DI affinity and DI/DS selectivity, respectively.
Journal of Medicinal Chemistry, 1994
The synthesis and in vitro evaluation of benzo-fused benzodiazepines 1-6 are described. These &am... more The synthesis and in vitro evaluation of benzo-fused benzodiazepines 1-6 are described. These "molecular yardsticks" were employed to probe the spatial dimensions of the lipophilic pocket L2 in the benzodiazepine receptor (BzR) cleft and to determine the effect of occupation of L2 with respect to agonist activity. Of the new analogs synthesized, the 7,8-benzo-fused benzodiazepine 6 displayed moderately high affinity for the BzR (IC50 = 55 nM) and exhibited both anticonvulsant (ED50 approximately 15 mg/kg) and muscle relaxant (ED50 approximately 15 mg/kg) activity. As expected, 2 and 4 interacted with the repulsive regions of interaction, S1 and S2, and exhibited low affinities for BzR. The rigid nature of these molecular yardsticks (especially 6, Figure 7) has been employed to probe the depth of L2. Moreover, in the case of 6 full occupation of L2 has resulted in an increase in the muscle relaxant effect at the expense of the anticonvulsant/anxiolytic effect.
Experimental and Molecular Therapeutics
Journal of medicinal chemistry, Jan 21, 2018
The nuclear hormone receptor RORC2 (also known as RORγt) is a promising target for the treatment ... more The nuclear hormone receptor RORC2 (also known as RORγt) is a promising target for the treatment of autoimmune diseases. A small molecule, inverse agonist of the receptor is anticipated to reduce production of IL-17, a key pro-inflammatory cytokine. Through a high-throughput screening approach, we identified a molecule displaying promising binding affinity for RORC2, inhibition of IL-17 production in Th17 cells, and selectivity against the related RORA and RORB receptor isoforms. Lead optimization to improve the potency and metabolic stability of this hit focused on two key design strategies, namely, iterative optimization driven by increasing lipophilic efficiency and structure-guided conformational restriction to achieve optimal ground state energetics and maximize receptor residence time. This approach successfully identified 3-cyano-N-(3-(1-isobutyrylpiperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide as a potent and selective RORC2 inverse agoni...
ChemInform
ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance t... more ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Bulletin des Sociétés Chimiques Belges, 1983
A new method for the preparation of p-lactams has been developed. The protocol involves 1,3-dipol... more A new method for the preparation of p-lactams has been developed. The protocol involves 1,3-dipolar cycloaddition of nitrones with nitro substituted alkenes followed by a subsequent reorganization of the resulting 5-nitroisoxazolidine isomer. The utilization of a-silyl substituted amines as azomethine ylide equivalents has also been explored.
Antiviral chemistry & chemotherapy, 2003
Hepatitis C virus (HCV) is a highly prevalent virus and one of the major agents of chronic hepati... more Hepatitis C virus (HCV) is a highly prevalent virus and one of the major agents of chronic hepatitis. Since HCV NS3 protease is essential for the processing of HCV polyprotein, this protease is a target of choice to control HCV replication. Peptide inhibitors of NS3 were developed by selective amino acid replacement of six leader sequences, corresponding to regions of HCV polyprotein that are cleaved by NS3. The large numbers of potential 14-mer and 16-mer peptide inhibitors thus obtained were tested against NS3 using the fluorescent probe RETS1 and peptide cofactor SVVIVGRIILSGRA from NS4A protein. This afforded several peptide inhibitors with an IC50 of around 2 microM. These peptides may be good leading compounds for the development of peptidomimetics to control HCV replication in the treatment of chronic hepatitis C.
Drug design and discovery, 1995
A unified pharmacophore model of the benzodiazepine receptor (BzR) has been developed using the t... more A unified pharmacophore model of the benzodiazepine receptor (BzR) has been developed using the techniques of chemical synthesis, radioligand binding, and receptor mapping. This model is based on 136 different ligands spanning ten structurally diverse classes of compounds and qualitatively accounts for the relative affinities, efficacies, and functional effects (agonism vs. antagonism vs. inverse agonism) displayed by various ligands at the BzR. In addition, the model is expanded to account for the pharmacology of a recently discovered BzR receptor subtype termed the 'Diazepam-Insensitive' (DI) BzR. Moreover, the unified model described here is compared and contrasted with other published pharmacophore models. As previously reported, the synthesis of both partial agonists and partial inverse agonists has been achieved by using parts of this model. Partial agonists are of interest as potentially improved agents for treatment of anxiety disorders, while the partial inverse ago...
Encyclopedia of Hormones, 2003
Journal of Medicinal Chemistry, 1992
... Allen,+ Anthony J. LaLoggia,t Linda J. Darn,&amp;#x27; Michael J. Martin,t Gabriele C... more ... Allen,+ Anthony J. LaLoggia,t Linda J. Darn,&amp;#x27; Michael J. Martin,t Gabriele Costantino,$ Timothy J. Hagen,g Konrad F. Koehler,&amp;#x27;J Phil Skolnick,* and ... equation will improve the fit to a training set of data, but inclusion of too many variables will often cause a sub-stantial reduction in ...
Proceedings of the National Academy of Sciences, 1986
The diterpene diester phorbol 12-myristate 13-acetate and the alkaloid teleocidin B are structura... more The diterpene diester phorbol 12-myristate 13-acetate and the alkaloid teleocidin B are structurally unrelated natural products that display similar potent irritant and tumor-promoting activities. Computer modeling of these and other structural classes of tumor promoters show a marked similarity in the relative positions of certain heteroatoms and hydrophobic groups. For phorbol this mapping consists of the C-4, C-9, and C-20 hydroxyl groups as well as a hydrophobic region frled by a long-chain acyl functionality attached to either the C-12 or the C-13 positions. Diacylglycerols, thought to be the endogenous activators of the major phorbol ester receptor protein kinase C likewise fit this model in a stereospecific fashion. As an initial test of the utility of the model, members of a new and simplified class of activators were synthesized that possess the predicted essential structural features. These compounds all inhibited specific phorbol ester binding to protein kinase C, albeit with low affinity (10-60 ,.M); further analysis of one derivative, decylhydroxylindole, confirmed that the inhibition of phorbol ester binding was competitive. This same derivative inhibited epidermal growth factor binding in intact Swiss 3T3 cells and studies with another derivative showed phosphorylation of a 40-kDa protein in platelets. Both of these in vivo responses are characteristic of phorbol esters.
Proceedings of the National Academy of Sciences, 1988
The bryostatins are macrocyclic lactones that represent an additional structural class of potent ... more The bryostatins are macrocyclic lactones that represent an additional structural class of potent activators of protein kinase C. These marine animal biosynthetic products are of unusual interest because they induce only a subset of the biological responses induced by the phorbol esters. We have now determined the binding affinities of naturally occurring and semisynthetic bryostatins for protein kinase C by competition analysis with [26-3Hlbryostatin 4 as the radioactive ligand. Esterification of the hydroxyl group at C26 caused dramatic loss of activity as did inversion of the asymmetric center at this position. In contrast, neither of the ester groups at C7 and C20 had a major influence on activity. Computer modeling of the phorbol esters, related diterpenes, and indole alkaloids suggested that the C20, C9, and C4 oxygens of phorbol represented critical elements of the phorbol ester pharmacophore. The C26 oxygen of the bryostatins, together with the C1 and C19 oxygens, gave an excellent spatial correlation with this model, with a root-mean-square deviation of 0.16 A (compared to 0.10-0.35 A among phorbol-related
Nature Reviews Drug Discovery, 2011
The two oestrogen receptor subtypes α and β are hormone-regulated modulators of intracellular sig... more The two oestrogen receptor subtypes α and β are hormone-regulated modulators of intracellular signalling and gene expression. Regulation of oestrogen receptor activity is crucial not only for development and homeostasis but also for the treatment of various diseases and symptoms. Classical selective oestrogen receptor modulators are well established in the treatment of breast cancer and osteoporosis, but emerging data suggest that the development of subtype-selective ligands that specifically target either oestrogen receptor-α or oestrogen receptor-β could be a more optimal approach for the treatment of cancer, cardiovascular disease, multiple sclerosis and Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease.
Molecular Endocrinology, 2005
Two-point mutations in the human glucocorticoid receptor have been studied by computer simulation... more Two-point mutations in the human glucocorticoid receptor have been studied by computer simulations to rationalize experimental data, where mutants comprising the V571M substitution improve both transcriptional activity and affinity for aldosterone despite large distances between the mutated residue and the coactivator-binding surface and ligand-binding pocket, respectively. Our molecular dynamics simulations show that the V571M mutation modifies the coactivator-binding site defined by helices 3, 4, and 12, and that specific structural rearrangement of the coactivator-binding site correlates well with transactivation data. A similar reorganization of the coactivator-binding cleft is observed in crystallographic structures of the estrogen receptor in the presence of coactiva-tor peptide, compared with structures without peptide, indicating that induced fit for coactivator binding is a general phenomenon for nuclear receptors. These results suggest that the V571M substitution facilitates recruitment of coactivator protein by promotion of a conformational substate reducing the energetic penalty for the induced fit of the receptor-coactivator complex. Furthermore, our simulations of V571M mutants showed reduced fluctuations of residues lining the ligandbinding pocket. This indicates that a reduction of the entropic cost for ligand binding may explain the increased affinity of V571M mutants for certain ligands. (Molecular Endocrinology 19: 1960-1977, 2005) N UCLEAR RECEPTORS are ligand-activated transcription factors that regulate the expression of target genes in a cell-and promoter-specific manner. Key to nuclear receptor activation by agonist ligands is positioning of the C-terminal ␣-helix [helix 12 H12)]) of the ligand-binding domain (LBD) in a conformation that promotes and prevents binding of coactivator and corepressor proteins, respectively (1). The glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) are homologous members of the steroid hormone receptor superfamily. Intriguingly, whereas the GR interacts primarily with glucocorticoid ligands, the MR is activated by both glucocorticoids and mineralocorticoids. Synthetic glucocorticoids are widely used in treatment of inflammatory and immune disorders, such as asthma, and mineralocorticoids are involved in regulation of the electrolytic balance, affecting renal function and blood pressure among others.
Life Sciences, 1991
In order to employ rational drug design in the discovery of selective benzodiazepine receptor ago... more In order to employ rational drug design in the discovery of selective benzodiazepine receptor agonists and inverse agonists, pharmacophore/receptor models for both these activities must first be established. Recently, a pharmacophore for the inverse agonist site has been formulated employing the most recent receptor mapping techniques (22). The continuation of this approach to the pharmacophore for agonist ligands has permitted a definition of this site independently of the inverse agonist model. The agonist pharmacophore/receptor contains two hydrogen bond donating sites of interaction (H1 and H2) located about 6.5 A from each other, as well as three areas of lipophilic interaction (L1-L3). The areas L1 and L2 are critical for agonist activity; moreover, some ligands also require an interaction in a third lipophilic area termed L3. This is in agreement with previous work (12-23). In addition, an area of negative steric interaction (S1) between the ligand and receptor-binding protein is defined. In regard to the pharmacophore, it was established that the alignment rule for agonist beta-carbolines is different from that which elicits inverse agonist activity. Consideration of the pharmacophore has resulted in the synthesis of a new beta-carboline 16 which elicits agonist activity. This ligand 16 not only satisfied the requirements of the pharmacophore, but more importantly it elicited both anticonvulsant and anxiolytic activity, but was devoid of the myorelaxant/ataxic properties associated with the benzodiazepines.
Journal of the American Chemical Society, 1981
The Journal of Organic Chemistry, 1987
... (26) Chan, TH; Fleming, I. Synthesis 1979, 761. (27) Padwa, A.; Carter, S. P.; Chiacchio, U.;... more ... (26) Chan, TH; Fleming, I. Synthesis 1979, 761. (27) Padwa, A.; Carter, S. P.; Chiacchio, U.; Kline, D. N. Tetrahedron Lett. ... (34) Ali, S. A.; Senaratne, PA; Illig, C. R.; Meckler, H.; Tufariello, (35) Padwa, A.; Fisera, L.; Koehler, KF; Rodriguez, A,; Wong, GK JJ Tetrahedron Lett. ...
The Journal of Organic Chemistry, 1984
Crystallographic Data a n d X-ray Structure Analysis of 13a. Crystals of 13a are triclinic, space... more Crystallographic Data a n d X-ray Structure Analysis of 13a. Crystals of 13a are triclinic, space group Pi: a = 10.91 (1) b = 9.570 (3), c = 8.758 (8) A; a = 65.15 (l), @ = 66.94 (31, y = 71.24 (1)O; 2 = 2; d, = 1.21 g ~m-~. Intensities were measured by using Mo Ka radiation [Philips PWllOO diffractometer, graphite monochromator, 8-28 scan mode, 3 < 8 < 25O, scan speed 0.025O s-', scan width deg 1.7 + 0.6 tan 81. The total number of independent reflexions measured was 2384. The structure was solved by direct methods3' and refined by full-matrix least-squares3, to a final R-factor of 4.8%. In the refinements 1934 reflections with intensities greater than the standard deviation from counting statistics were used. Hydrogen atoms were found from difference Fourier syntheses. In the last cycles 263 parameters were refined (scale factor, extinction parameter, positional
The Journal of Organic Chemistry, 1984
Journal of Medicinal Chemistry, 1993
Several 1,4-diazepines were recently reported to bind with high affinities to the "diaze... more Several 1,4-diazepines were recently reported to bind with high affinities to the "diazepam-insensitive" (DI) isoform of the benzodiazepine receptor (BzR) (Korpi, E.R.; Uusi-Oukari, M.; Wegelius, K. Eur. J. Pharm. 1992, 213, 323-329. Wong, G.; Skolnick, P. Eur. J. Pharmacol. Mol. Pharm. Sec. 1992, 225, 63-68). However, only the putative ethanol antagonist 1 (Ro 15-4513) displayed modest selectivity for the DI site compared to other "diazepam-sensitive" (DS) BzR isoforms. In order to probe the requirements for selective, high-affinity binding to the DI site, the affinities of 47 benzodiazepines have been determined at both DI and DS BzR sites. In addition, single X-ray crystallographic analyses for three of these derivatives, 5 (Ro 17-1812), 6 (Ro 16-6028), and 42 (Ro 14-5974), are reported. The radioligand binding studies reveal that modifications to the 3-, 7-, and 8-positions of 6-oxoimidazo[1,5-alpha] [1,4]benzodiazepines have a marked influence on the Ki(DI)/Ki(DS) ratios. In order to more precisely determine the structural requirements for both high affinity and selectivity at DI BzR relative to DS, 3D-QSAR analyses were carried out on ligand affinities at both of these BzR isoforms. This analysis was based, in part, on the new X-ray crystallographic data. Satisfactory cross-validated regression equations were obtained individually for the logarithms of ligand affinities at DI and DS as well as for the differences of the logarithms of their affinities at these two isoforms (cross-validated R2 > 0.70 for all three regression equations). The steric and electrostatic 3D-QSAR DI and DS maps are in qualitative accord with the structure-activity relationship (SAR) data. Furthermore, the DI and DI/DS maps may be useful in the design of ligands with enhanced DI affinity and DI/DS selectivity, respectively.
Journal of Medicinal Chemistry, 1994
The synthesis and in vitro evaluation of benzo-fused benzodiazepines 1-6 are described. These &am... more The synthesis and in vitro evaluation of benzo-fused benzodiazepines 1-6 are described. These "molecular yardsticks" were employed to probe the spatial dimensions of the lipophilic pocket L2 in the benzodiazepine receptor (BzR) cleft and to determine the effect of occupation of L2 with respect to agonist activity. Of the new analogs synthesized, the 7,8-benzo-fused benzodiazepine 6 displayed moderately high affinity for the BzR (IC50 = 55 nM) and exhibited both anticonvulsant (ED50 approximately 15 mg/kg) and muscle relaxant (ED50 approximately 15 mg/kg) activity. As expected, 2 and 4 interacted with the repulsive regions of interaction, S1 and S2, and exhibited low affinities for BzR. The rigid nature of these molecular yardsticks (especially 6, Figure 7) has been employed to probe the depth of L2. Moreover, in the case of 6 full occupation of L2 has resulted in an increase in the muscle relaxant effect at the expense of the anticonvulsant/anxiolytic effect.