- Hybridization of β-Adrenergic Agonists and Antagonists Confers G Protein Bias
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Starting from the β-adrenoceptor agonist isoprenaline and beta-blocker carvedilol, we designed and synthesized three different chemotypes of agonist/antagonist hybrids. Investigations of ligand-mediated receptor activation using bioluminescence resonance energy transfer biosensors revealed a predominant effect of the aromatic head group on the intrinsic activity of our ligands, as ligands with a carvedilol head group were devoid of agonistic activity. Ligands composed of a catechol head group and an antagonist-like oxypropylene spacer possess significant intrinsic activity for the activation of Gαs, while they only show weak or even no β-arrestin-2 recruitment at both β1- and β2-AR. Molecular dynamics simulations suggest that the difference in G protein efficacy and β-arrestin recruitment of the hybrid (S)-22, the full agonist epinephrine, and the β2-selective, G protein-biased partial agonist salmeterol depends on specific hydrogen bonding between Ser5.46 and Asn6.55, and the aromatic head group of the ligands.
- Stanek, Markus,Picard, Louis-Philippe,Schmidt, Maximilian F.,Kaindl, Jonas M.,Hübner, Harald,Bouvier, Michel,Weikert, Dorothée,Gmeiner, Peter
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p. 5111 - 5131
(2019/05/28)
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- Synthesis of Glycoborine, Glybomine A and B, the Phytoalexin Carbalexin A and the β-Adrenoreceptor Antagonists Carazolol and Carvedilol
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We describe a regioselective synthesis of 4- or 5-substituted carbazoles by oxidative cyclisation of meta-oxygen-substituted N-phenylanilines. Using the regiodirecting effect of a pivaloyloxy group, we prepared 4-hydroxycarbazole, a precursor for the enantiospecific synthesis of the β-adrenoreceptor antagonists (?)-(S)-carazolol (5) and (?)-(S)-carvedilol (6). Regioselective palladium(II)-catalysed cyclisation of different diarylamines led to total synthesis of glycoborine (7) and the first total syntheses of the phytoalexin carbalexin A (8), glybomine A (9) and glybomine B (10). For glybomine B (10), a 5-hydroxycarbazole was converted into the corresponding triflate and utilized for introduction of a prenyl substituent.
- Brütting, Christian,Hesse, Ronny,J?ger, Anne,Kataeva, Olga,Schmidt, Arndt W.,Kn?lker, Hans-Joachim
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p. 16897 - 16911
(2016/11/17)
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- BETA-3 RECEPTOR LIGANDS AND THEIR USE IN THERAPY
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The present invention relates to new compounds, ligands of the beta-3 adrenergic receptor, their preparation and their use in therapy or as research tools for said receptor; the invention also relates to a process for the preparation of the compounds of the invention and the use of inverse agonists of the beta-3 adrenergic receptor as medicaments.
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Page/Page column 12
(2010/04/23)
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- BRIDGED ARYL PIPERAZINES DERIVATIVES USEFUL FOR THE TREATMENT OF CNS, GI-URINARY AND REPRODUCTIVE DISORDERS
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The present invention is directed to bridged aryl piperazine derivatives, pharmaceutical compositions containing them and their use in the treatment of depression and related disorders. The compounds of the present invention are serotonin transport inhibi
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Page/Page column 26
(2010/11/30)
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- NOVEL HETEROCYCLIC COMPOUNDS AS PSTAT3/IL-6 INHIBITORS
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The present invention relates to novel heterocyclic compounds of the general formula (I), as IL-6 inhibitors, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their hydrates, their solvates, their pharmaceutically acceptable salts and compositions, their metabolites and prodrugs thereof. The present invention more particularly provides novel heterocyclic compounds of the general formula (I). Also included is a method for treatment of cancer, cancer cachexia and inflammatory diseases including immunological diseases, particularly those mediated by cytokines such as IL-6, through pSTAT3 inhibition, in a mammal comprising administering an effective amount of a compound of formula (I) as described above.
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Page/Page column 28
(2010/11/27)
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- Novel heterocyclic compounds as pSTAT3/IL-6 inhibitors
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The present invention relates to novel heterocyclic compounds of the general formula (I), as IL-6 inhibitors, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their hydrates, their solvates, their pharmaceutically acceptable salts and compositions, their metabolites and prodrugs thereof. The present invention more particularly provides novel heterocyclic compounds of the general formula (I). Also included is a method for treatment of cancer, cancer cachexia and inflammatory diseases including immunological diseases, particularly those mediated by cytokines such as IL-6, through pSTAT3 inhibition, in a mammal comprising administering an effective amount of a compound of formula (I) as described above.
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Page/Page column 16
(2010/11/27)
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- CARDIOTONIC COMPOUNDS WITH INHIBITORY ACTIVITY AGAINST BETA-ADRENERGIC RECEPTORS AND PHOSPHODIESTERASE
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The present invention provides compounds possessing inhibitory activity against ? adrenergic receptors and phosphodiesterase (PDE), including type 3 phosphodiesterase (PDE-3). The present invention further provides pharmaceutical compositions comprising s
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Page/Page column 37-38
(2010/11/08)
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- 2- ( (2, 3-DIHYDROXYPROPYL) AMINOMETHYL) CHROMANE DERIVATIVES FOR USE AS BETA-3 ADRENORECEPTOR AGONISTS IN THE TREATMENT OF UROLOGICAL AND INFLAMMATORY DISORDERS
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This invention relates to chroman derivatives of formula (I) and salts thereof which are useful as active ingredients of pharmaceutical preparations. The chroman derivatives of the present invention have an excellent activity as BETA 3 antagonists and are useful for the prophylaxis and treatment of diseases associated with BETA 3 activity, in particular for the treatment of urological disorder or disease, such as detrusor overactivity (overactive bladder), urinary incontinence, neurogenic detrusor overactivity (detrusor hyperflexia), idiopathic detrusor overactivity (detrusor instability), benign prostatic hyperplasia, and lower urinary tract symptoms; and inflammatory disorders, such as asthma and COPD.
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Page/Page column 56
(2010/02/12)
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- Synthesis of β3 adrenergic receptor agonist LY377604 and its metabolite 4-hydroxycarbazole, labeled with carbon-14 and deuterium
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Synthesis of 14C-radiolabeled 4-hydroxycarbazole was accomplished starting from aniline-[U-14C], based on zinc chloride initiated Fischer cyclization of the phenylhydrazone prepared from phenylhydrazine-[U-14C] and cyclohexane-1,3-dione. The resulting tetrahydrooxocarbazole was subjected to dehydrogenation-aromatization using palladium on carbon. The aromatized 4-hydroxycarbazole-[4b,5,6,7,8,8a- 14C] was then used for the synthesis of 14C-labeled β3 adrenergic receptor agonist LY377604. The introduction of four deuteria in the carbazole fragment of LY377604 accomplished by its initial bromination and subsequent catalytic deuteration of the resulting tetrabromide. A similar approach was used for the conversion of 4-hydroxycarbazole into its tetradeutero-isotopomer. Copyright
- Czeskis, Boris A.,Wheeler, William J.
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p. 407 - 419
(2007/10/03)
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- Novel substituted 4-aminomethylpiperidines as potent and selective human β3-agonists. Part 1: Aryloxypropanolaminomethylpiperidines
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The synthesis and SAR of a series of human β3 adrenoreceptor agonists based on a template derived from a common pharmacophore coupled with 4-aminomethylpiperidine is described. Potent and selective agents were identified such as 26 that was in vitro active in CHO cells expressing human β3-AR (EC50=49 nM, IA=1.1), and in vivo active in a transgenic mouse model.
- Steffan, Robert J.,Ashwell, Mark A.,Solvibile, William R.,Matelan, Edward,Largis, Elwood,Han, Stella,Tillet, Jeffery,Mulvey, Ruth
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p. 2957 - 2961
(2007/10/03)
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- Potent, selective aminothiazolidinediones agonists of the human β3 Adrenergic receptor
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A cloned human β3 adrenergic receptor assay was used to identify potent and selective β3 agonists. The thiazolidinedione moiety has been identified as a new pharmacophore for the human β3 adrenergic receptor. The versatility of the thiazolidinedione pharmacophore was demonstrated in both the arylethanolamine and phenylpropanolamine families of β3 agonists, where potent and selective compounds have been synthesized. Thiazolidinedione 20, a potent and selective human β3 agonist, increased thermogenesis and lowered plasma glucose levels in the db/db mice.
- Malamas,Largis,Gunawan,Li,Tillett,Han,Mulvey
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p. 164 - 177
(2007/10/03)
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- Synthesis and in vitro and in vivo characteristics of an iodinated analogue of the β-adrenoceptor antagonist carazolol
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A new (radio)iodinated, β-adrenoceptor ligand, (S)-(-)-4-[3-[(1,1- dimethyl-3-iodo-(2E)-propenyl)-amino]-2-hydroxypropoxy]carbazole (CYBL8E, 1), was prepared. 1 is an iodinated analogue of the high-affinity β- adrenoceptor antagonist carazolol (2). The asymmetric synthesis was achieved in four steps starting from 4-hydroxycarbazole. The iodine-123-labeled form was obtained by an iododestannylation reaction with [123I]NaI in the presence of H2O2. Using classical in vitro displacement experiments with membrane fractions of cardiac left ventricular muscle, 1 proved to have a high affinity for the receptor (K(i) = 0.31 ± 0.03). Biodistribution studies performed in New Zealand white rabbits demonstrated the specificity of the binding in vivo to the receptor. Uptake of [123I]1 was reduced significantly in both atrial muscle, left ventricular muscle, frontal cortex, cerebellum, and striatum, by the pretreatment of the animals with different β-adrenoceptor antagonists. In conclusion, 1 is a potent nonselective β-adrenoceptor antagonist, which binds specifically to the β- adrenoceptor in vivo, and is therefore a promising radioligand for the imaging of β-adrenoceptors using single photon emission computerized tomography.
- Dubois, Eric A.,Van Den Bos, Jan C.,Doornbos, Tamme,Van Doremalen, Peter A. P. M.,Somsen, G. Aernout,Vekemans, Jozef A. J. M.,Janssen, Anton G. M.,Batink, Harry D.,Boer, Gerard J.,Pfaffendorf, Martin,Van Royen, Eric A.,Van Zwieten, Pieter A.
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p. 3256 - 3262
(2007/10/03)
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