Discovery of a Novel and Potent Human and Rat .BETA.3-Adrenergic Receptor Agonist, [3-[(2R)-[[(2R)-(3-Chlorophenyl)-2-hydroxyethyl]amino]propyl]-1H-indol-7-yloxy]acetic Acid
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Accession number;05A0106838
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| Title;Discovery of a Novel and Potent Human and Rat .BETA.3-Adrenergic Receptor Agonist, [3-[(2R)-[[(2R)-(3-Chlorophenyl)-2-hydroxyethyl]amino]propyl]-1H-indol-7-yloxy]acetic Acid |
| Author;
HARADA H
(Dainippon Pharmaceutical Co. Ltd., Osaka, Jpn)
HIROKAWA Y
(Dainippon Pharmaceutical Co. Ltd., Osaka, Jpn)
SUZUKI K
(Dainippon Pharmaceutical Co. Ltd., Osaka, Jpn)
HIYAMA Y
(Dainippon Pharmaceutical Co. Ltd., Osaka, Jpn)
OUE M
(Dainippon Pharmaceutical Co. Ltd., Osaka, Jpn)
KAWASHIMA H
(Dainippon Pharmaceutical Co. Ltd., Osaka, Jpn)
KATO H
(Dainippon Pharmaceutical Co. Ltd., Osaka, Jpn)
YOSHIDA N
(Dainippon Pharmaceutical Co. Ltd., Osaka, Jpn)
FURUTANI Y
(Dainippon Pharmaceutical Co. Ltd., Osaka, Jpn)
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Journal Title;Chem Pharm Bull
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Journal Code:G0504A
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ISSN:0009-2363
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VOL.53;NO.2;PAGE.184-198(2005)
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| Figure&Table&Reference;FIG.3, TBL.6, REF.85 |
| Pub. Country;Japan |
| Language;English |
| Abstract;In search for potent and selective .BETA.3-adrenergic receptor (.BETA.3-AR) agonists as potential drugs for the treatment of type II diabetes and obesity, a novel series of 1-(3-chlorophenyl)-2-aminoethanol derivatives were prepared and evaluated for their biological activity at human .BETA.1-, .BETA.2-, and .BETA.3-ARs and rat .BETA.3-AR expressed in Chinese hamster ovary (CHO) cells. Replacement of the right-hand side (RHS, benzene ring) in the 'first generation' .BETA.3-AR agonists BRL 37344 and CL 316243 with a 1H-indole ring gave compound 31 with unique pharmacological properties among .BETA.3-AR agonists. Initial in vitro assays showed that 31 possesses modest rat and human .BETA.3-ARs agonistic activity. Introduction of various substituent into the indole nucleus of 31 afforded a number of compounds with good .BETA.3-ARs agonistic activity. In particular, 90 having a carboxylic acid functionality at the 7-position of the indole nucleus showed the most potent human .BETA.3-AR agonistic activity. Finally, optical resolution of 90 led to the identification of the most promising compound, [3-[(2R)-[[(2R)-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-1H-indol-7-yloxy]acetic acid (96, AJ-9677). This compound exhibited potent human .BETA.3-AR agonistic activity (EC50=0.062 nM, IA=116%) with 210- and 103-fold selectivity over human .BETA.2-AR and .BETA.1-AR, respectively. Compound 96 also exhibited potent rat .BETA.3-AR agonistic activity (EC50=0.016 nM, IA=110%). Moreover, repeated oral administration of 96 inhibited body weight gain and significantly decreased glucose, insulin, free fatty acid, and triglyceride concentrations in plasma in KK-Ay/Ta mice. On the basis of this pharmacological profile, 96 entered clinical development as a drug for the treatment of type II diabetes and obesity. (author abst.) |
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