Discovery of a Novel and Potent Human and Rat β_3-Adrenergic Receptor Agonist, [3-[(2R)-[[(2R)-(3-Chlorophenyl)-2-hydroxyethyl]amino]propyl]-1H-indol-7-yloxy]acetic Acid

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In search for potent and selective β_3-adrenergic receptor (β_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 β_1-, β_2-, and β_3-ARs and rat β_3-AR expressed in Chinese hamster ovary (CHO) cells. Replacement of the right-hand side (RHS, benzene ring) in the 'first generation' β_3-AR agonists BRL 37344 and CL 316243 with a 1H-indole ring gave compound 31 with unique pharmacological properties among β_3-AR agonists. Initial in vitro assays showed that 31 possesses modest rat and human β_3-ARs agonistic activity. Introduction of various substituent into the indole nucleus of 31 afforded a number of compounds with good β_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 β_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 β_3-AR agonistic activity (EC_<50>=0.062 nM, IA=116%) with 210- and 103-fold selectivity over human β_2-AR and β_1-AR, respectively. Compound 96 also exhibited potent rat β_3-AR agonistic activity (EC_<50>=0.016nM, IA=10%). 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-A^y/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.
社団法人日本薬学会の論文
2005-02-01

Discovery of a Novel and Potent Human and Rat β_3-Adrenergic Receptor Agonist, [3-[(2R)-[[(2R)-(3-Chlorophenyl)-2-hydroxyethyl]amino]propyl]-1H-indol-7-yloxy]acetic Acid

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