- Synthesis and in vitro and in vivo characterization of highly β1-selective β-adrenoceptor partial agonists
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β-Adrenoceptor antagonists boast a 50-year use for symptomatic control in numerous cardiovascular diseases. One might expect highly selective antagonists are available for the human β-adrenoceptor subtype involved in these diseases, yet few truly β1-selective molecules exist. To address this clinical need, we re-evaluated LK 204-545 (1),(1) a selective β1-adrenoceptor antagonist, and discovered it possessed significant partial agonism. Removal of 1's aromatic nitrile afforded 19, a ligand with similar β1-adrenoceptor selectivity and partial agonism (log KD of -7.75 and -5.15 as an antagonist of functional β1- and β2-mediated responses, respectively, and 34% of the maximal response of isoprenaline (β1)). In vitro β-adrenoceptor selectivity and partial agonism of 19 were mirrored in vivo. We designed analogues of 19 to improve affinity, selectivity, and partial agonism. Although partial agonism could not be fully attenuated, SAR suggests that an extended alkoxyalkoxy side chain, alongside substituents at the meta- or para-positions of the phenylurea, increases ligand affinity and β1-selectivity.
- Mistry, Shailesh N.,Baker, Jillian G.,Fischer, Peter M.,Hill, Stephen J.,Gardiner, Sheila M.,Kellam, Barrie
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p. 3852 - 3865
(2013/07/05)
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- PHENOXYPROPANOL DERIVATIVES AND THEIR USE IN TREATING CARDIAC AND CARDIOVASCULAR DISEASES
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A compound of formula I-0, and its pharmaceutically acceptable salt or salts and physiologically hydrolysable derivatives in free form or salt form: wherein Z1 is C1-C4 linear or branched alkyl or alkenyl; R4 is selected from unsubstituted and substituted C3-C8 cycloalkyl, C1-C8 linear or branched alkyl, C2-5 alkenyl, C6-C10 heteroaryl or aryl, or C3-C8 heterocyclyl which may be part unsaturated, and combinations thereof; is linear C2-3 alkylene,; X1 is selected from NH and O; X2 is selected from unsaturated C and unsaturated S; and X3 is selected from NH and CH2; or one of X1 and X3 is a single bond; or X1 is O and X2 and X3 together are a single bond; and R7 is selected from oxo, F, Cl, Br, CN, NH2, NR92, NO2, CF3, OR9, COR9, OCOR9, COOR9, NR9COR9, CONR92 SO2NR92, NR9SO2R9; and R8 is selected from C1-5 alkyl, C1-5 alkoxyl, C2-5 alkenyl or alkynyl, C6-10) aryl and C3-8 cycloalkyl and combinations thereof, which may be unsubstituted or f urther substituted by one or more F, Cl, Br, CN, NH2, NR32, NO2, CF3; and R9 is selected from H and a group R8 as hereinbefore defined; n7 and n8 and the sum thereof are independently selected from zero and the whole number integer 1 to 4; processes for the preparation thereof, compositions and uses.
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- 3-amino-propoxphenyl derivatives (I)
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Compounds of formula (Ia) as potent, β1-specific beta blockers with a short duration of action in the systemic circulation, wherein R is 3′,4′-dimethoxyphenyl, R1 is hydrogen, and R2 is selected from methyl, ethyl, propyl,
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- 3-AMINO-PROPOXYPHENYL DERIVATIVES (I)
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Compounds of formula (Ia) as potent, β1-specific beta blockers with a short duration of action in the systemic circulation, wherein R is 3′,4′-dimethoxyphenyl. R1 is hydrogen, and R2 is selected from methyl, ethyl, propyl,
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- Synthesis, β-adrenoceptor pharmacology and toxicology of S-(-)-1-(4-(2-ethoxyethoxy)phenoxy)-2-hydroxy-3-(2-(3,4-dimethoxyphenyl) ethylamino)propane hydrochloride, a short acting β1-specific antagonist
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The synthesis of S-(-)-1-(4-(2-ethoxyethoxy)phenoxy)-2-hydroxy-3-(2-(3,4-dimethoxyphenyl) ethylamino)propane hydrochloride (D140S·HCl 6), a novel short acting β1-specific adrenoceptor antagonist, has been described. The antagonist potency for D140S·HCl 6 has been compared with esmolol, another short acting agent, and other well known β-adrenoceptor antagonists in isolated rat tissue preparations. The pharmacokinetics of D140S·HCl 6 in 7 day continuous intravenous infusions and 4 weeks intravenous bolus injection studies in conscious rats and dogs have been examined in toxicology studies. The effect on the isoprenaline-induced heart rate increase and the pharmacodynamic half-life of D140S·HCl 6 has been compared with esmolol in a conscious rat model. In addition, the results of a range of toxicological studies are presented. The results indicate that D140S·HCl 6 is a highly specific β1-adrenoceptor antagonist (pA2=8.15±0.22, β1/β2 selectivity>4400). The in vitro studies suggest D140S·HCl is ca. ten times more potent and 60 times more β1-specific than racemic esmolol. Pharmacokinetic non-linearity was seen when given as a 7 day intravenous infusion at toxicological doses above 10 mg kg-1 h-1 in the rat and 2.5 mg kg-1 h-1 in the dog. Both D140S·HCl 6 and esmolol have very short durations of action after intravenous infusion in the rat (pharmacodynamic half-life is 15 min for D140S·HCl and 10 min for esmolol). The toxicological tests indicate that D140S·HCl 6 shows no unexpected toxicity and none of the tissue irritancy problems reported for esmolol formulations.
- Jackman, Graham P.,Iakovidis, Dimitri,Nero, Tracy L.,Anavekar, Nagesh S.,Rezmann-Vitti, Linda A.,Louis, Simon N.S.,Mori, Masanori,Drummer, Olaf H.,Louis, William J.
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p. 731 - 741
(2007/10/03)
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- Enhancing the aqueous solubility of d4T-based phosphoramidate prodrugs
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A range of polyether para-substituted phosphoramidates were synthesised and found to have substantially elevated aqueous solubilities compared to the underivatised parent prodrug. A 30-fold increase in aqueous solubility could be achieved without a substantial decrease of in vitro activity against HIV-1. Replacement of the aryl (i.e. phenolic) moiety by tyrosine led to a substantial enhancement in aqueous solubility but also to a decrease in antiviral potency. A previously unobserved trend was identified, relating increased aryl substituent steric bulk to decreased antiviral activity. (C) 2000 Elsevier Science Ltd. All rights reserved.
- Siddiqui, Adam,McGuigan, Christopher,Ballatore, Carlo,Srinivasan, Sheila,De Clercq, Erik,Balzarini, Jan
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p. 381 - 384
(2007/10/03)
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- DERIVATIVES OF 1-PHENOXY-3-AMINO-PROPAN-2-OL
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The present invention relates to new pharmacologically valuable derivatives of 1-phenoxy-3-amino-propan-2-ol having the formula STR1 wherein X denotes STR2 A denotes--CH 2--alkoxy,--O--alkoxyalkyl,--O--hydroxyalkyl or STR3 AN AROMATIC OR QUASI-AROMATIC, 5
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