Discovery of a Novel Series of Biphenyl Benzoic Acid Derivatives as Potent and Selective Human β3-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: Washington, DC American Chemical Society 27.03.2008
• Subjects: Biological and medical sciences; Catecholaminergic system; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Agonist; Rat; Monkey; Selectivity; Structure activity relation; Chlorine Organic compounds; Primates; Overactive bladder; Intraduodenal administration; Chemical synthesis; Dog; Human; Fissipedia; Carnivora; Urinary system disease; Aminoalcohol; Ether; Rodentia; Benzene derivatives; β3-Adrenergic receptor; Oral administration; Urinary tract disease; Bioavailability; In vitro; In vivo; Vertebrata; Chemotherapy; Experimental disease; Mammalia; Treatment; Animal; Affinity; Bladder disease; Pharmacokinetics
• ISSN: 0022-2623; 1520-4804
• 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 β3 adrenergic receptor (β3-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 β3-AR agonists.