Discovery of a novel and potent human and rat β3-adrenergic receptor agonist, [3-[(2R)-[[(2R)-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl] -1H-indol-7-yloxy]acetic acid

Article abstract of DOI:10.1248/cpb.53.184

In search for potent and selective β₃-adrenergic receptor (β₃-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 β₁-, β₂-, and β₃-ARs and rat β₃-AR expressed in Chinese hamster ovary (CHO) cells. Replacement of the right-hand side (RHS, benzene ring) in the 'first generation' β₃-AR agonists BRL 37344 and CL 316243 with a 1H-indole ring gave compound 31 with unique pharmacological properties among β₃-AR agonists. Initial in vitro assays showed that 31 possesses modest rat and human β₃-ARs agonistic activity. Introduction of various substituent into the indole nucleus of 31 afforded a number of compounds with good β₃-ARs agonistic activity. In particular, 90 having a carboxylic acid functionality at the 7-position of the indole nucleus showed the most potent human β₃-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 β₃-AR agonistic activity (EC₅₀ = 0.062 nM, IA = 116%) with 210- and 103-fold selectivity over human β₂-AR and β₁-AR, respectively. Compound 96 also exhibited potent rat β₃-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-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.