Discovery of a novel series of biphenyl benzoic acid derivatives as potent and selective human beta3-adrenergic receptor agonists with good oral bioavailability. Part I

• Published in: Journal of medicinal chemistry Vol. 51; no. 6; pp. 1925 - 1944
• Main Authors: Imanishi, Masashi, Tomishima, Yasuyo, Itou, Shinji, Hamashima, Hitoshi, Nakajima, Yutaka, Washizuka, Kenichi, Sakurai, Minoru, Matsui, Shigeo, Imamura, Emiko, Ueshima, Koji, Yamamoto, Takao, Yamamoto, Nobuhiro, Ishikawa, Hirofumi, Nakano, Keiko, Unami, Naoko, Hamada, Kaori, Matsumura, Yasuhiro, Takamura, Fujiko, Hattori, Kouji
• Format: Journal Article
• Language: English
• Published: United States 27.03.2008
• Subjects: Administration, Oral; Adrenergic beta-3 Receptor Agonists; Adrenergic beta-Agonists - chemical synthesis; Adrenergic beta-Agonists - chemistry; Adrenergic beta-Agonists - pharmacology; Anesthesia; Animals; Benzoates - chemical synthesis; Benzoates - chemistry; Benzoates - pharmacology; Biological Availability; Biphenyl Compounds - chemistry; Blood Pressure - drug effects; Carbachol - antagonists & inhibitors; Carbachol - pharmacology; Dogs; Drug Design; Drug Evaluation, Preclinical; Female; Humans; Injections, Intravenous; Models, Animal; Molecular Structure; Stereoisomerism; Structure-Activity Relationship; Time Factors
• ISSN: 0022-2623
• DOI: 10.1021/jm701324c

A novel class of biphenyl analogues containing a benzoic acid moiety based on lead compound 8i have been identified as potent and selective human beta 3 adrenergic receptor (beta 3-AR) agonists with good oral bioavailability and long plasma half-life. After further substituent effects were investigated at the terminal phenyl ring of lead compound 8i, we have discovered that more lipophilic substitution at the R position improved potency and selectivity. As a result of these studies, 10a and 10e were identified as the leading candidates with the best balance of potency, selectivity, and pharmacokinetic profiles. In addition, compounds 10a and 10e were evaluated to be efficacious for a carbachol-induced increase of intravesical pressure, such as an overactive bladder model in anesthetized dogs. This represents the first demonstrated result dealing with beta 3-AR agonists.