title: Discovery of a novel and potent human and rat beta3-adrenergic receptor agonist, [3-[(2R)-[[(2R)-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-1H-indol-7-yloxy]acetic acid.
abstract: In search for potent and selective beta3-adrenergic receptor (beta3-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 beta1-, beta2-, and beta3-ARs and rat beta3-AR expressed in Chinese hamster ovary (CHO) cells. Replacement of the right-hand side (RHS, benzene ring) in the 'first generation' beta3-AR agonists BRL 37344 and CL 316243 with a 1H-indole ring gave compound 31 with unique pharmacological properties among beta3-AR agonists. Initial in vitro assays showed that 31 possesses modest rat and human beta3-ARs agonistic activity. Introduction of various substituent into the indole nucleus of 31 afforded a number of compounds with good beta3-ARs agonistic activity. In particular, 90 having a carboxylic acid functionality at the 7-position of the indole nucleus showed the most potent human beta3-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 beta3-AR agonistic activity (EC50=0.062 nM, IA=116%) with 210- and 103-fold selectivity over human beta2-AR and beta1-AR, respectively. Compound 96 also exhibited potent rat beta3-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.
authors.affiliation: Chemistry Research Laboratories, Dainippon Pharmaceutical Co. Ltd, Osaka, Japan. hiroshi-harada@dainippon-pharm.co.jp
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Harada
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Hirokawa
authors.forename: Kenji
authors.initials: K
authors.lastname: Suzuki
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Hiyama
authors.forename: Mayumi
authors.initials: M
authors.lastname: Oue
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kawashima
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kato
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Yoshida
authors.forename: Yasuji
authors.initials: Y
authors.lastname: Furutani
authors.forename: Shiro
authors.initials: S
authors.lastname: Kato
mesh_terms: D000085:Acetates / Q000138:chemical synthesis* / Q000494:pharmacology*; D058667:Adrenergic beta-3 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D003106:Colon / Q000187:drug effects; D018360:Crystallography, X-Ray; D000242:Cyclic AMP / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000097:blood; D006801:Humans; D007202:Indicators and Reagents; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D007328:Insulin / Q000097:blood; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D009765:Obesity / Q000188:drug therapy; D051381:Rats; D013329:Structure-Activity Relationship; D014280:Triglycerides / Q000097:blood
chemical_list: C418363:((3-((2R)-(((2R)-3-chlorophenyl)-2-hydroxyethyl)amino)propyl)-1H-indol-7-yloxy)acetic acid; D000085:Acetates; D058667:Adrenergic beta-3 Receptor Agonists; D000318:Adrenergic beta-Agonists; D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D007202:Indicators and Reagents; D007211:Indoles; D007328:Insulin; D014280:Triglycerides; D000242:Cyclic AMP