179819-93-3Relevant academic research and scientific papers
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
Harada, Hiroshi,Hirokawa, Yoshimi,Suzuki, Kenji,Hiyama, Yoichi,Oue, Mayumi,Kawashima, Hitoshi,Kato, Hiroshi,Yoshida, Naoyuki,Furutani, Yasuji,Kato, Shiro
, p. 184 - 198 (2007/10/03)
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-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.
Novel and potent human and rat β3-adrenergic receptor agonists containing substituted 3-indolylalkylamines
Harada, Hiroshi,Hirokawa, Yoshimi,Suzuki, Kenji,Hiyama, Yoichi,Oue, Mayumi,Kawashima, Hitoshi,Yoshida, Naoyuki,Furutani, Yasuji,Kato, Shiro
, p. 1301 - 1305 (2007/10/03)
A novel series of 2-(3-indolyl)alkylamino-1-(3-chlorophenyl)ethanols was prepared and evaluated for in vitro ability to stimulate cAMP production in Chinese hamster ovary cells expressing cloned human β3-AR. The optically active 30a was found to be the most potent and selective human β3-AR agonist in this series with an EC50 value of 0.062 nM. In addition, 30a selectivity for human β3-AR was 210-fold and 103-fold that for human β2-AR and β1-AR, respectively. Furthermore, 30a showed potent agonistic activity at rat β3-AR.
A scalable synthesis of (R)-3-(2-aminopropyl)-7-benzyloxyindole via resolution
Fujii, Akihito,Fujima, Yoshito,Harada, Hiroshi,Ikunaka, Masaya,Inoue, Toru,Kato, Shiro,Matsuyama, Keisuke
, p. 3235 - 3240 (2007/10/03)
(±)-3-(2-Aminopropyl)-7-benzyloxyindole 1, assembled from 7-benzyloxyindole 3 in 59% overall yield, is resolved with O,O′-di-p-toluoyl L-(2R,3R)-tartaric acid 7 into (R)-1, a key intermediate of AJ-9677 2 (selective adrenaline β3-agonist) in 99
