- Chemoenzymatic synthesis of (S)-Pindolol using lipases
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A straightforward chemoenzymatic synthesis of (S)-Pindolol has been developed. The key step involved the enzymatic kinetic resolution of rac-2-acetoxy-1-(1H-indol-4-yloxy)-3-chloropropane with lipase from Pseudomonas fluorescens via hydrolytic process to obtain enantiomerically enriched halohydrin (2S)-1-(1H-indol-4-yloxy)-3-chloro-2-propanol (96% ee) and (2R)-2-acetoxy-1-(1H-indol-4-yloxy)-3-chloropropane (97% ee). The latter was subjected to a hydrolysis reaction catalyzed by Candida rugosa leading to (2R)-1-(1H-indol-4-yloxy)-3-chloro-2-propanol (97% ee), followed by a reaction with isopropylamine, producing (S)-Pindolol (97% ee) in quantitative yield.
- Lima, Gledson Vieira,da Silva, Marcos Reinaldo,de Sousa Fonseca, Thiago,de Lima, Leandro Bezerra,de Oliveira, Maria da Concei??o Ferreira,de Lemos, Telma Leda Gomes,Zampieri, Davila,dos Santos, Jose Cleiton Sousa,Rios, Nathalia Saraiva,Gon?alves, Luciana Rocha Barros,Molinari, Francesco,de Mattos, Marcos Carlos
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- Synthesis and pharmacological activity of a new series of 1-(1H-indol-4-yloxy)-3-(2-(2-methoxyphenoxy)ethylamino)-propan-2-ol analogs
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β-Adrenergic receptor antagonists are important therapeutics for the treatment of cardiovascular disorders. In the group of β-blockers, much attention is being paid to the third-generation drugs that possess important ancillary properties besides inhibiting β-adrenoceptors. Vasodilating activity of these drugs is produced through different mechanisms, such as nitric oxide (NO) release, β2-agonistic action, α1-blockade, antioxidant action, and Ca2t entry blockade. Here, a study on evaluation of the cardiovascular activity of five new compounds is presented. Compound 3a is a methyl and four of the tested compounds (3b–e) are dimethoxy derivatives of 1-(1H-indol-4-yloxy)-3-(2-(2-methoxyphenoxy)-ethylamino)propan-2-ol. The obtained results confirmed that the methyl and dimethoxy derivatives of 1-(1H-indol-4-yloxy)-3-(2-(2-methoxyphenoxy)ethylamino)propan-2-ol and their enantiomers possess α1- and β1-adrenolytic activities and that the antiarrhythmic and hypotensive effects of the tested compounds are related to their adrenolytic properties.
- Bednarski, Marek,Otto, Monika,Dudek, Magdalena,Ko?aczkowski, Marcin,Bucki, Adam,Siwek, Agata,Groszek, Gra?yna,Maziarz, El?bieta,Wilk, Piotr,Sapa, Jacek
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p. 211 - 223
(2018/05/08)
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- STORE OVERLOAD-INDUCED CALCIUM RELEASE INHIBITORS AND METHODS FOR PRODUCING AND USING THE SAME
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The present invention provides compounds having store overload-induced Ca2+ release (SOICR) inhibitory activity and methods for producing and using the same. In particular, compounds of the invention is of the formula: R1-X1-L-X2-R2, wherein R1, X1, L, X2, and R2 are those defined herein.
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- Novel carvedilol analogues that suppress store-overload-induced Ca 2+ release
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Carvedilol is a uniquely effective drug for the treatment of cardiac arrhythmias in patients with heart failure. This activity is in part because of its ability to inhibit store-overload-induced calcium release (SOICR) through the RyR2 channel. We describe the synthesis, characterization, and bioassay of ca. 100 compounds based on the carvedilol motif to identify features that correlate with and optimize SOICR inhibition. A single-cell bioassay was employed on the basis of the RyR2-R4496C mutant HEK-293 cell line in which calcium release from the endoplasmic reticulum through the defective channel was measured. IC50 values for SOICR inhibition were thus obtained. The compounds investigated contained modifications to the three principal subunits of carvedilol, including the carbazole and catechol moieties, as well as the linker chain containing the β-amino alcohol functionality. The SAR results indicate that significant alterations are tolerated in each of the three subunits.
- Smith, Chris D.,Wang, Aixia,Vembaiyan, Kannan,Zhang, Jingqun,Xie, Cuihong,Zhou, Qiang,Wu, Guogen,Chen, S. R. Wayne,Back, Thomas G.
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p. 8626 - 8655
(2013/12/04)
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- Synthesis and characterization of high-affinity 4,4-difluoro-4-bora-3a,4a- diaza-s-indacene-labeled fluorescent ligands for human β-adrenoceptors
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The growing practice of exploiting noninvasive fluorescence-based techniques to study G protein-coupled receptor pharmacology at the single cell and single molecule level demands the availability of high-quality fluorescent ligands. To this end, this study evaluated a new series of red-emitting ligands for the human β-adrenoceptor family. Upon the basis of the orthosteric ligands propranolol, alprenolol, and pindolol, the synthesized linker-modified congeners were coupled to the commercially available fluorophore BODIPY 630/650-X. This yielded high-affinity β-adrenoceptor fluorescent ligands for both the propranolol and alprenolol derivatives; however, the pindolol-based products displayed lower affinity. A fluorescent diethylene glycol linked propranolol derivative (18a) had the highest affinity (log KD of -9.53 and -8.46 as an antagonist of functional β2- and β1-mediated responses, respectively). Imaging studies with this compound further confirmed that it can be employed to selectively label the human β2-adrenoceptor in single living cells, with receptor-associated binding prevented by preincubation with the nonfluorescent β2-selective antagonist 3-(isopropylamino)-1-[(7- methyl-4-indanyl)oxy]butan-2-ol (ICI 118551) (J. Cardiovasc. Pharmacol.1983, 5, 430-437.)
- Baker, Jillian G.,Adams, Luke A.,Salchow, Karolina,Mistry, Shailesh N.,Middleton, Richard J.,Hill, Stephen J.,Kellam, Barrie
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experimental part
p. 6874 - 6887
(2011/12/15)
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- A vHTS approach for the identification of β-adrenoceptor ligands
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Using a vHTS based on a pharmacophore alignment on known β3-adrenoceptor ligands, a set of intriguing β-adrenoceptor ligands was identified, optimization of which resulted in a selective and potent human β2-AR antagonist.
- Tasler, Stefan,Baumgartner, Roland,Aschenbrenner, Andrea,Ammendola, Astrid,Wolf, Kristina,Wieber, Tanja,Schachtner, Josef,Blisse, Marcus,Quotschalla, Udo,Ney, Peter
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scheme or table
p. 3399 - 3404
(2010/08/06)
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- Synthesis and adrenolytic activity of 1-(1H-indol-4-yloxy)-3-{[2-(2-methoxyphenoxy)ethyl]amino}propan-2-ol and its enantiomers. Part 1
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The synthesis of (2RS)-1-(1H-indol-4-yloxy)-3-{[2-(2-methoxyphenoxy)ethyl]amino}propan-2-ol ((RS)-9) and its enantiomers has been described and tested for electrocardiographic, antiarrhythmic, hypotensive and spasmolytic activities as well as for α1-, α2- and β1-adrenoceptors' binding affinities. All compounds significantly decrease systolic and diastolic blood pressure, and possess antiarrhythmic activity and affinity to α1-, α2- and β1-adrenoceptors. The results suggest that the antiarrhythmic and hypotensive effects of these compounds are related to their adrenolytic but not spasmolytic properties.
- Groszek, Grazyna,Bednarski, Marek,Dybala, Malgorzata,Filipek, Barbara
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experimental part
p. 809 - 817
(2009/09/05)
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- Indoloxypropanolamine analogues as 5-HT1A receptor antagonists
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Analogues of pindolol, 1-(1H-indol-4-yloxy)-3-isopropylamino-propan-2-ol, were synthesized and evaluated as 5-HT1A receptor antagonists. The structural features required for optimal binding to the 5-HT1A receptor are as follows: S-2-propanol linker, 4-indoloxy substituent, and a large lipophilic cyclic amine substituent.
- Krushinski Jr., Joseph H.,Schaus, John M.,Thompson, Dennis C.,Calligaro, David O.,Nelson, David L.,Luecke, Susan H.,Wainscott, David B.,Wong, David T.
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p. 5600 - 5604
(2008/03/14)
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- SMALL MOLECULE INHIBITORS OF HER2 EXPRESSION
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Peptide mimetic small molecule inhibitors of Sur-2 are provided having the general formula (I).
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Page/Page column 38; Sheet 29
(2008/06/13)
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- Small molecule inhibitors of HER2 expression
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Peptide mimetic small molecule inhibitors of Sur-2 are provided having the general formula:
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- A Wrench-Shaped Synthetic Molecule that Modulates a Transcription Factor-Coactivator Interaction
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Development of synthetic molecules that provide external control over the transcription of a given gene represents a challenge in medicinal and bioorganic chemistry. Here we report design and analysis of wrenchnolol, a wrench-shaped synthetic molecule that impairs the transcription of the Her2 oncogene by disrupting association of transcription factor ESX with its coactivator Sur-2. The "jaw" part of the compound mimics the α-helical interface of the activation domain of ESX, and the "handle" region accepts chemical modifications for a range of analysis. A water-soluble handle permitted NMR study in aqueous solution; a biotinylated handle verified the selectivity of the interaction, and a fluorescent handle confirmed the cell permeability of the compound. The case study of wrenchnolol foreshadows the promise and the challenge of targeting protein-protein interactions in the nucleus and may lead to the development of unique synthetic modulators of gene transcription.
- Shimogawa, Hiroki,Kwon, Youngjoo,Mao, Qian,Kawazoe, Yoshinori,Choi, Yongmun,Asada, Shinichi,Kigoshi, Hideo,Uesugi, Motonari
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p. 3461 - 3471
(2007/10/03)
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- Small molecule inhibitors of HER2 expression
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Peptide mimetic small molecule inhibitors of Sur-2 are provided having the general formula:
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- Process for the preparation of 3-amino-2-hydroxy-1-propyl ethers
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PCT No. PCT/JP97/03220 Sec. 371 Date Apr. 28, 1999 Sec. 102(e) Date Apr. 28, 1999 PCT Filed Sep. 12, 1997 PCT Pub. No. WO98/12171 PCT Pub. Date Mar. 26, 1998A process for preparation of 3-amino-2-hydroxy-1-propyl ether of the formula wherein R1 is substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclic ring, R2 and R3 are the same or different hydrogen atom, a substituted or unsubstituted alkyl, or may form a ring together with an adjacent nitrogen atom, which ring may be interrupted with nitrogen atom, oxygen atom or sulfur atom, which is characterized in reacting an epoxy compound of the formula wherein X is halogen, in the presence of a fluoride salt, with an alcohol and then reacting an amine. According to the above method, an intermediates for synthesis of medicines is obtained in good yield and highly optical purity.
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- Process for preparation of glycidyl ether
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PCT No. PCT/JP97/03221 Sec. 371 Date Apr. 29, 1999 Sec. 102(e) Date Apr. 29, 1999 PCT Filed Sep. 12, 1997 PCT Pub. No. WO98/12186 PCT Pub. Date Mar. 26, 1998A process for preparation of a glycidyl ether which is characrelized in reacting an epoxy compound of the formula wherein X is halogen or sulfonyloxy in the presence of a fluoride salt, with an alcohol. According to the above method, glycigyl ethers or their optically active compounds important as intermediates for synthesis of medicines are easily obtained in good yield and especially the optically active compounds are obtained with highly optical purity.
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- Design and synthesis of new potent, silent 5-HT(1A) antagonists by covalent coupling of aminopropanol derivatives with selective serotonin reuptake inhibitors
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Hybrid molecules built up by covalent coupling of aminopropanol derivatives (especially pindolol) with antidepressant drags like fluoxetine, paroxetine or milnacipran were found to be potent and silent 5-HT(1A) antagonists (K(B) 1 nM for 7c and 9a).
- Perez,Pauwels,Pallard-Sigogneau,Fourrier,Chopin,Palmier,Colovray,Halazy
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p. 3423 - 3428
(2007/10/03)
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- Design and synthesis of a series of combined vasodilator/β-adrenoceptor antagonists based on 6-arylpyridazinones
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A series of new 6-[4-[[(aryloxy)acyl]amino]phenyl]-4,5-dihydropyridazinones have been synthesized and evaluated as combined vasodilator/β-adrenoceptor antagonists and potential antihypertensive agents. Many of the early compounds displayed an unacceptably high level of intrinsic sympathomimetic activity (ISA) and a relatively short duration of action. Disubstitution in the 2,3-positions or in the 4-position of the aryloxy ring gave compounds with low ISA levels and, in some instances, improved duration of action. All of the compounds were vasodilators, but the 5-methylpyridazinone derivatives showed consistently greater antihypertensive activity than their 5-H lower homologues. Further detailed pharmacological investigations led to the selection of 6-[4-[3-[[2-hydroxy-3-[4-[2-(cyclopropylmethoxy)ethyl]phenoxy]propyl]amino ]propionamido]phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone (4t) (SK&F 95018) as a development candidate.
- Slater,Howson,Swayne,Taylor,Reavill
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p. 345 - 351
(2007/10/02)
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- Affinity Labels for β-Adrenoreceptors: Preparation and Properties of Alkylating β-Blockers Derived from Indole
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New alkylating ligands derived from indole with high affinity for β-adrenoceptors were synthesized and their properties examined.N8-(Bromoacetyl)-N1--(Z)-1,8-diamino-p-menthane (8) and its N1,N8 isomer (9) were prepared by the reaction of bromoacetyl bromide with a product of the condensation of 4-indolyl glycidyl ether with (Z)-1,8-diamino-p-menthane.A similar reaction employing 2-cyano-4-indolyl glycidyl ether yielded the respective cyano derivatives 10 and 11.Apparent affinities (Ki, M) for β-adrenoreceptors on membrane preparations from rat heart and lung were 4.6*10-10 and 1.34*10-9 for 8, 2.3*10-8 and 4.5*10-9 for 9, 6.1*10-10 and 1.49*10-9 for 10, and 1.83*10-9 and 2.78*10-9 for 11, respectively.When membranes were preincubated with the above ligands (1*10-8 M, 30 min, 30 deg C) and then washed extensively, reduction in the concentration of specific binding sites of dihydroalprenolol ranged from 7percent to 76percent and there was no change in KD of the remaining binding sites. (+/-)-Alprenolol and (-)-isoproterenol, but not (+)-isoproterenol, when included with the alkylating ligands in the preincubation mixtures, prevented the reduction in concentration of dihydroalprenolol binding sites.Compounds 8-11 alone did not stimulate adenylate cyclase activity in rat heart homogenates.However, these compounds inhibited (-)-isoproterenol-stimulated adenylate cyclase activity with Ki values ranging between 5*10-9 and 60*10-9 M.These results suggest that high-affinity irreversible β-adrenergic antagonists were obtained that may be useful for in vivo studies of β-adrenoceptors.
- Pitha, Josef,Buchowiecki, Wieslaw,Milecki, Jan,Kusiak, John W.
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p. 612 - 615
(2007/10/02)
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- DERIVATIVES OF BETA-ADRENERGIC ANTAGONISTS
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Molecular structures of β-adrenergic antagonists are modified to produce biologically active compounds. The β-antagonists are modified to form molecules of the general structure: STR1 wherein R is most generally R"--OCH 2--, and in some instances is R"--, and R"=an aryl or substituted aryl moiety; R'=--H,--CH 3, or a short chain alkyl moiety; and Y=--OH, or more usually,--OAX or--NHAX, where A=an alkyl, aryl, or aralkyl moiety, and X=a terminal grouping, such as--CH 3,--CF 3 or--(CH 2) n COOH; or AX may be a carrier moiety consisting of a defined peptide or protein. "
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- CARBAMYLPIPERAZINE COMPOUNDS
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4-(3-Aryloxy-2-hydroxypropyl)piperazines bearing a carbamyl group in the 1-position are β-adrenergic blockers. A typical example is 1-carbamyl-4-{3-2-allyl-3-(2-carbethoxyaminoethyl)phenoxy!-2-hydroxypropyl} piperazine.
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- Synthesis and characterization of iodoazidobenzylpindolol
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A high affinity β-adrenergic ligand, iodoazidobenzylpindolol, was synthesized and characterized. The absorption spectrum of this compound changed markedly upon photolysis consistent with decomposition of the azide group. This compound has a K(D) of 5-7 x 10-10M for the duck erythrocyte ghost β-adrenergic receptor when measured in a competitive binding assay.
- Rashidbaigi,Ruoho
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p. 305 - 307
(2007/10/02)
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- Basic substituted xanthine derivatives
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There are prepared compounds corresponding to the general formula in which T represents a theophyllinyl-(7) or theobrominyl-(1) radical, Alk is a linear or branched alkylene group with 2 to 5 carbon atoms which may also be substituted by a hydroxy group and Ar represents an aromatic monocyclic or condensed bicyclic, carbocyclic or heterocyclic radical optionally substituted by one or more alkyl groups with 1 to 6 carbon atoms, alkenyl groups with 2 to 6 carbon atoms, alkinyl groups with 2 to 6 carbon atoms, hydroxy groups, acyloxy groups with 1 to 6 carbon atoms, alkoxy groups with 1 to 6 carbon atoms, alkenoxy groups with 2 to 6 carbon atoms, phenyl radicals, halogen atoms, amino groups, acyl groups with 2 to 6 carbon atoms, aminocarbonyl groups, ureido groups, acyl amino groups with 1 to 6 carbon atoms, cycloalkyl groups with 3 to 8 carbon atoms or by one or more cycloalkenyl groups with 4 to 8 carbon atoms, the heterocyclic radical consisting of individual rings with 5 to 6 members and containing from 1 to 4 heteroatoms, and their pharmaceutically acceptable salts. The compounds have beta-adrenolytic activity.
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