Discovery of novel series of benzoic acid derivatives containing biphenyl ether moiety as potent and selective human beta(3)-adrenergic receptor agonists: Part IV

• Published in: Bioorganic & medicinal chemistry letters 2008-09, Vol.18 (18), p.5037-5040
• Main Authors: Nakajima, Yutaka, Imanishi, Masashi, Itou, Shinji, Hamashima, Hitoshi, Tomishima, Yasuyo, Washizuka, Kenichi, Sakurai, Minoru, Matsui, Shigeo, Imamura, Emiko, Ueshima, Koji, Yamamoto, Takao, Yamamoto, Nobuhiro, Ishikawa, Hirofumi, Nakano, Keiko, Unami, Naoko, Hamada, Kaori, Hattori, Kouji
• Format: Article
• Language: English
• Subjects: Adrenergic Agonists - chemical synthesis; Adrenergic Agonists - chemistry; Adrenergic Agonists - pharmacology; Adrenergic beta-3 Receptor Agonists; Animals; Benzoates - chemical synthesis; Benzoates - chemistry; Benzoates - pharmacology; Biphenyl Compounds - chemical synthesis; Biphenyl Compounds - chemistry; Biphenyl Compounds - pharmacology; Combinatorial Chemistry Techniques; Disease Models, Animal; Dogs; Humans; Molecular Structure; Stereoisomerism; Structure-Activity Relationship
• ISSN: 1464-3405
• DOI: 10.1016/j.bmcl.2008.08.009

Identification and SAR study of novel series of beta(3)-AR agonists with benzoic acid are described. Conversion of ether linkage position of phenoxybenzoic acid derivative 2b led to compound 7b with moderate beta(3)-AR activity. Further modification in right, center and left parts of compound 7b was investigated to improve the beta(3)-AR potency and selectivity. Compounds 7g and 7k, with the bulky aliphatic-substituted group at 2-position of benzoic acid moiety, were identified as potent and selective beta(3)-AR agonists. In addition, in vivo efficacy of compounds 7g and 7k was exhibited on dog OAB model.