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
| Accession number;05A0106838 |
| 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) |
Journal Title;Chem Pharm Bull
|
Journal Code:G0504A
|
ISSN:0009-2363
|
|
VOL.53;NO.2;PAGE.184-198(2005)
|
| 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.) |
|
|
