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Matthew J Barnes,
Christian Burschka,
Matthias W Büttner,
Richard Conroy, Jürgen O Daiss,
Ian C Gray,
Alan G Hendrick,
L H Tam,
Diana Kuehn,
David J Miller,
John S Mills,
Philip Mitchell,
John G Montana,
Parameswary A Muniandy,
Helen Rapley,
Graham A Showell,
David Tebbe,
Reinhold Tacke,
Julie B H Warneck,
Bin Zhu
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ABSTRACT: AG-045572 (CMPD1, 1 a) is a nonpeptidic gonadotropin-releasing hormone (GnRH) antagonist that has been investigated for the treatment of sex hormone-related diseases. In the context of systematic studies on sila-substituted drugs, the silicon analogue disila-AG-045572 (1 b) and its derivative 2 were prepared in multi-step syntheses and characterized by elemental analyses (C, H, N), NMR spectroscopic studies (1H, 13C, 29Si), and single-crystal X-ray diffraction. The pharmacological properties of compounds 1 a, 1 b, and 2 were compared in terms of their in vitro potency at cloned human and rat GnRH receptors. Compounds 1 a and 2 were also examined in regard to their pharmacokinetics and in vivo efficacy in both castrated rat (luteinizing hormone (LH) suppression) and intact rat (testosterone suppression) models. The efficacy and pharmacokinetic profiles of 1 a and its silicon-containing analogue 2 appear similar, indicating that replacement of the 5,6,7,8-tetrahydronaphthalene ring system by the 1,3-disilaindane skeleton led to retention of efficacy. Therefore, the silicon compound 2 represents a novel drug prototype for the design of potent, orally available GnRH antagonists suitable for once-daily dosing.
ChemMedChem 09/2011; 6(11):2070-80. · 3.15 Impact Factor
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Julie B Warneck,
Frankie H M Cheng,
Matthew J Barnes,
John S Mills,
John G Montana,
Robert J Naylor,
Man-P Ngan,
Man-K Wai, Jürgen O Daiss,
Reinhold Tacke,
John A Rudd
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ABSTRACT: The chemotherapeutic drug cisplatin is associated with severe gastrointestinal toxicity that can last for several days. A recent strategy to treat the nausea and emesis includes the combination of a 5-HT3 receptor antagonist, a glucocorticoid, and an NK1 receptor antagonist. The present studies explore the use of the selective noradrenaline reuptake inhibitors, (R)-sila-venlafaxine, (R,R)-reboxetine and (S,S)-reboxetine to prevent cisplatin (5 mg/kg, i.p.)-induced acute (0-24 h) and delayed (24-72 h) emesis in ferrets. The positive control regimen of ondansetron and dexamethasone, both at 1 mg/kg/8 h, reduced acute and delayed emesis by 100 (P<0.001) and 61% (P<0.05). (R)-sila-venlafaxine at 5 and 15 mg/kg/4 h reduced acute emesis by 86 (P<0.01) and 66% (P<0.05), respectively and both enantiomers of reboxetine at 1 mg/kg/12 h also reduced the response by approximately 70-90% (P<0.05). Out of the reuptake inhibitors, only (R)-sila-venlafaxine at 15 mg/kg/4 h was active to reduce delayed emesis (a 57% reduction was observed (P<0.05)); its terminal plasma levels were positively correlated with an inhibition of emesis during the delayed phase (P<0.05). (R)-sila-venlafaxine was also examined against a higher dose of cisplatin 10 mg/kg, i.p. (3 h test) and it dose-dependently antagonized the response (maximum reduction was 94% at 10 mg/kg, p.o.; P<0.01) but it was ineffective against apomorphine (0.125 mg/kg, s.c.) and ipecacuanha (2 mg/kg, p.o.)-induced emesis (P>0.05). In conclusion, the studies provide the first evidence for an anti-emetic potential of noradrenaline reuptake inhibitors to reduce chemotherapy-induced acute and delayed emesis.
Toxicology and Applied Pharmacology 07/2008; 232(3):369-75. · 4.45 Impact Factor
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ABSTRACT: A series of triorganyl(2,4,6-trimethoxyphenyl)silanes containing various combinations of acid-labile protecting groups for silicon, including allyl, 2,6-dimethoxyphenyl, mesityl, 4-methoxyphenyl, 1-naphthyl, and phenyl, were synthesized and characterized. These compounds served as reagents in a series of experiments to determine the selectivity of the cleavage of the 2,4,6-trimethoxyphenyl group in the presence of the aforementioned groups using an ethereal hydrogen chloride solution to obtain synthetically useful chlorosilanes. Additionally, the silylation potential of trimethyl-, methyldiphenyl-, and triethyl(2,4,6-trimethoxyphenyl)silane under mild (0−35 °C), acidic conditions with O-, N-, and S-nucleophiles was examined. These silylation reagents exhibit both chemo- and regioselectivity with respect to the tested nucleophiles, are neither moisture nor air sensitive and thus easy to handle, and produce a relatively inert byproduct, 1,3,5-trimethoxybenzene, which is recyclable.
10/2007;
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Matthias W Büttner,
Christian Burschka, Jürgen O Daiss,
Diana Ivanova,
Natacha Rochel,
Sabrina Kammerer,
Carole Peluso-Iltis,
Audrey Bindler,
Claudine Gaudon,
Pierre Germain,
Dino Moras,
Hinrich Gronemeyer,
Reinhold Tacke
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ABSTRACT: Twofold sila-substitution (C/Si exchange) in the saturated ring of the tetrahydronaphthalene skeleton of the retinoid agonists TTNPB (1 a) and 3-methyl-TTNPB (2 a) leads to disila-TTNPB (1 b) and disila-3-methyl-TTNPB (2 b), respectively. The silicon compounds 1 b and 2 b were synthesized in multiple steps, and their identities were established by elemental analyses, multinuclear NMR experiments, and single-crystal X-ray diffraction studies. Like TTNPB (1 a) and 3-methyl-TTNPB (2 a), the analogous silicon-based arotinoids 1 b and 2 b are strong pan-RAR agonists and display the same strong differentiation and apoptosis-inducing activity in NB4 promyelocytic leukemia cells as the parent carbon compounds. These results are in keeping with the nearly isomorphous structures of 1 a and 1 b bound to the complex of the RARbeta ligand-binding domain with the nuclear receptor (NR) box 2 peptide of the SRC-1 coactivator. The contacts within the ligand-binding pocket are identical except for helix H11, for which two turns are shifted in the disila-TTNPB (1 b) complex. This study represents the first comprehensive structure-function analysis of a carbon/silicon switch in a signaling molecule and demonstrates that silicon analogues can have the same biological functionalities and conserved structures as their parent carbon compounds, and it illustrates at the same time that silicon analogues of biologically active compounds have the potential to induce alternative allosteric effects, as in the case of helix H11, which might allow for novel options in drug design.
ChemBioChem 10/2007; 8(14):1688-99. · 3.94 Impact Factor
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ABSTRACT: Sila-substitution of drugs (the carbon/silicon switch) is a concept that is being successfully used for the development of new chemical entities. The (R)-sila-analogue of the antidepressant venlafaxine is devoid of the serotonin reuptake inhibition observed with the marketed drug, leading to a selective noradrenaline reuptake inhibitor displaying anti-emetic properties.
Bioorganic & Medicinal Chemistry Letters 06/2006; 16(9):2555-8. · 2.55 Impact Factor
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ABSTRACT: The serotonin/noradrenaline reuptake inhibitor rac-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexan-1-ol (rac-venlafaxine, rac-1a) is in clinical use as an antidepressant. The silicon analogue, rac-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]-1-silacyclohexan-1-ol (rac-sila-venlafaxine, rac-1b), was synthesized in multistep syntheses, starting from tetrachlorosilane or tetramethoxysilane. The corresponding 1-silacyclopentan-1-ol derivative rac-2 was prepared analogously. The sila-venlafaxine enantiomers (R)-1b and (S)-1b were obtained by resolution of rac-1b, using (+)- or (−)-10-camphorsulfonic acid as the resolving agent. Compounds rac-1b, (R)-1b, (S)-1b, rac-1b·HCl, (R)-1b·HCl, (S)-1b·HCl, (R)-1b·HBr, rac-2, and rac-2·HCl were characterized by multinuclear NMR studies and elemental analyses, and rac-1b·HCl, (R)-1b·HBr, and rac-2 were additionally characterized by crystal structure analyses. Compounds rac-1a, rac-1b, rac-2, (R)-1a, (S)-1a, (R)-1b, and (S)-1b were tested as their hydrochlorides for their efficacy in serotonin, noradrenaline, and dopamine reuptake inhibition assays. Sila-substitution (C/Si switch) of compounds rac-1a, (R)-1a, and (S)-1a (→ rac-1b, (R)-1b, (S)-1b) was found to dramatically influence their pharmacological selectivity profiles with respect to serotonin, noradrenaline, and dopamine reuptake inhibition. (R)-Sila-venlafaxine ((R)-1b) was identified to have a refined selectivity profile consistent with selective noradrenaline reuptake inhibition. Compounds with this profile may provide therapeutic benefit in the treatment of various nervous system disorders.
02/2006;
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ABSTRACT: Twofold sila-substitution (C/Si exchange) in the saturated ring of the tetrahydronaphthalene skeleton of the RXR-selective retinoid agonist bexarotene (1a) leads to disila-bexarotene (1b). Compound 1b was synthesized in a multistep synthesis, starting from 1,2-bis(chlorodimethylsilyl)ethane. The identity of 1b was established by elemental analyses and multinuclear NMR studies, and the C/Si analogues 1a and 1b (and an intermediate in the synthesis of 1b) were structurally characterized by single-crystal X-ray diffraction. Furthermore, 1a and 1b were studied for their interaction with retinoid X receptors. Although the twofold sila-substitution of 1a resulted in significant differences in the molecular structures of 1a and 1b, disila-bexarotene (1b) was shown to be a highly potent RXR agonist.
05/2005;
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ABSTRACT: N,N,N‘,N‘-Tetramethyl-N,N‘-bis(3-phthalimidopropyl)hexane-1,6-diaminium bromide (W84, 1) is an allosteric agent for the “common allosteric site” of muscarinic M2 receptors that slows the dissociation of the orthosteric ligand [3H]N-methylscopolamine ([3H]NMS) and submaximally diminishes [3H]NMS binding. The silicon-containing W84 derivatives (6-(dimethyl(3-(1,8-naphthalimido)propyl)silyl)hexyl)dimethyl(3-(1,8-naphthalimido)propyl)ammonium bromide (5) and (6-(dimethyl(3-(1,8-naphthalimido)propyl)silyl)hexyl)methyl(3-(1,8-naphthalimido)propyl)amine (6; isolated as 6·HCl) were synthesized in four-step syntheses, starting from ClMe2SiH. In contrast to W84 (1) (a 2-fold positively charged agent) and compound 5 (a singly positively charged agent), compound 6 is an uncharged allosteric modulator for ligand binding to muscarinic M2 receptors. Similar to 5, the action of 6 is characterized by an enhancement of [3H]NMS binding.
11/2004;
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ABSTRACT: A series of multifunctional (chloromethyl)silanes have been synthesized: Cl2Si(CH2Cl)2 (1), (MeO)2Si(CH2Cl)2 (2), tris(chloromethyl)(2,4,6-trimethoxyphenyl)silane (3), ClSi(CH2Cl)3 (4), MeOSi(CH2Cl)3 (5), Si(CH2Cl)4 (6), and ClCH2CH2Si(CH2Cl)3 (7). The synthesis of these compounds is based on coupling reactions between (chloromethyl)lithium, generated in situ from bromochloromethane and n-butyllithium in tetrahydrofuran, and chlorosilanes. Compounds 1−7 were characterized by NMR studies (1H, 13C, 29Si) and elemental analyses, and 3 and 6 were additionally studied by single-crystal X-ray diffraction. Silanes with more than one SiCH2Cl moiety and compounds of this type with additional Si-functional groups are of great interest for synthetic organosilicon chemistry.
09/2004;
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ABSTRACT: The Si-2,4,6-trimethoxyphenyl (Si-2,4,6-TMOP) moiety is claimed to be an effective protecting group for synthetic organosilicon chemistry. To demonstrate its high synthetic potential, the Si-2,4,6-TMOP protecting group has been used for a novel multistep synthesis of rac-sila-venlafaxine (a sila-analogue of the serotonin/noradrenaline reuptake inhibitor rac-venlafaxine), starting from 1,1-dichloro-1-silacyclohexane. In addition, the Si-2,4,6-TMOP moiety has been used as a protecting group in silacyclobutane chemistry.
09/2004;
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ABSTRACT: The C/Si analogues 2-methyl-2-(3-methylbenzyl)but-3-en-1-ol (2a) and (hydroxymethyl)methyl(3-methylbenzyl)vinylsilane (2b) are chiral derivatives of the achiral fragrance materials majantol (1a) and sila-majantol (1b). Compounds 2a and 2b were synthesized as racemates, and the respective (+)- and (−)-enantiomers were obtained by chromatographic resolution (HPLC) of rac-2a and rac-2b using a chiral stationary phase. The enantiomerically pure compounds (+)-2a, (−)-2a, (+)-2b, and (−)-2b (optical rotations determined in methanol) were studied for their sensory properties. Both the odor character and the odor intensity of the silicon compounds (+)-2b and (−)-2b differ totally from those of the respective carbon analogues (+)-2a and (−)-2a.
09/2003;
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ABSTRACT: W84 (1) is an allosteric agent for the “common allosteric site” of muscarinic M2 receptors, its allosteric action being characterized by an inhibition of [3H]N-methylscopolamine ([3H]NMS) dissociation. A series of silicon-based derivatives of 1 (compounds 2−7) were synthesized and studied for their allosteric interaction with porcine heart muscarinic M2 receptors. Compound 2 (2-fold isosteric N+/Si exchange in the molecular framework of 1) and compounds 3−7 (single isosteric N+/Si exchange, varying (CH2)n chain length (n = 4−8) between the N and Si atom) were prepared by two-step (2) or four-step (3−7) syntheses, starting from ClSiMe2H (synthesis of 2) or ClSiMe2(CH2)3Cl (syntheses of 3−7). The identities of 2−7 were established by elemental analyses (C, H, N), NMR studies (1H, 13C, 15N, 29Si), and MS experiments. In addition, the solvate 3·MeC(O)Me was structurally characterized by single-crystal X-ray diffraction. The electrostatically neutral compound 2 did not interfere with the muscarinic M2 receptors, whereas the dicationic agent W84 (1) and the monocationic derivatives 3−7 inhibited [3H]NMS dissociation. W84 (1) decreased [3H]NMS equilibrium binding (negative cooperativity), whereas the silicon compound 5 enhanced [3H]NMS equilibrium binding (positive cooperativity); i.e., exchange of one positively charged nitrogen atom in 1 by a silicon atom switched the allosteric action from negative to positive cooperativity. The silicon compounds 3, 4, and 6 enhanced [3H]NMS equilibrium binding as well, whereas 7 behaved similarly to W84 (1).
01/2002;
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Julie B. Warneck,
Frankie H.M. Cheng,
Matthew J. Barnes,
John S. Mills,
John G. Montana,
Robert J. Naylor,
Man-P. Ngan,
Man-K. Wai, Jürgen O. Daiss,
Reinhold Tacke,
John A. Rudd
[show abstract]
[hide abstract]
ABSTRACT: The chemotherapeutic drug cisplatin is associated with severe gastrointestinal toxicity that can last for several days. A recent strategy to treat the nausea and emesis includes the combination of a 5-HT3 receptor antagonist, a glucocorticoid, and an NK1 receptor antagonist. The present studies explore the use of the selective noradrenaline reuptake inhibitors, (R)-sila-venlafaxine, (R,R)-reboxetine and (S,S)-reboxetine to prevent cisplatin (5 mg/kg, i.p.)-induced acute (0–24 h) and delayed (24–72 h) emesis in ferrets. The positive control regimen of ondansetron and dexamethasone, both at 1 mg/kg/8 h, reduced acute and delayed emesis by 100 (P < 0.001) and 61% (P < 0.05). (R)-sila-venlafaxine at 5 and 15 mg/kg/4 h reduced acute emesis by 86 (P < 0.01) and 66% (P < 0.05), respectively and both enantiomers of reboxetine at 1 mg/kg/12 h also reduced the response by ∼ 70–90% (P < 0.05). Out of the reuptake inhibitors, only (R)-sila-venlafaxine at 15 mg/kg/4 h was active to reduce delayed emesis (a 57% reduction was observed (P < 0.05)); its terminal plasma levels were positively correlated with an inhibition of emesis during the delayed phase (P < 0.05). (R)-sila-venlafaxine was also examined against a higher dose of cisplatin 10 mg/kg, i.p. (3 h test) and it dose-dependently antagonized the response (maximum reduction was 94% at 10 mg/kg, p.o.; P < 0.01) but it was ineffective against apomorphine (0.125 mg/kg, s.c.) and ipecacuanha (2 mg/kg, p.o.)-induced emesis (P > 0.05). In conclusion, the studies provide the first evidence for an anti-emetic potential of noradrenaline reuptake inhibitors to reduce chemotherapy-induced acute and delayed emesis.
Toxicology and Applied Pharmacology.
