title: 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.
abstract: 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.
authors.affiliation: Chemistry Research Laboratories, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Imanishi
authors.forename: Yasuyo
authors.initials: Y
authors.lastname: Tomishima
authors.forename: Shinji
authors.initials: S
authors.lastname: Itou
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Hamashima
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Nakajima
authors.forename: Kenichi
authors.initials: K
authors.lastname: Washizuka
authors.forename: Minoru
authors.initials: M
authors.lastname: Sakurai
authors.forename: Shigeo
authors.initials: S
authors.lastname: Matsui
authors.forename: Emiko
authors.initials: E
authors.lastname: Imamura
authors.forename: Koji
authors.initials: K
authors.lastname: Ueshima
authors.forename: Takao
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Ishikawa
authors.forename: Keiko
authors.initials: K
authors.lastname: Nakano
authors.forename: Naoko
authors.initials: N
authors.lastname: Unami
authors.forename: Kaori
authors.initials: K
authors.lastname: Hamada
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Matsumura
authors.forename: Fujiko
authors.initials: F
authors.lastname: Takamura
authors.forename: Kouji
authors.initials: K
authors.lastname: Hattori
mesh_terms: D000284:Administration, Oral; D058667:Adrenergic beta-3 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000758:Anesthesia; D000818:Animals; D001565:Benzoates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001682:Biological Availability; D001713:Biphenyl Compounds / Q000737:chemistry*; D001794:Blood Pressure / Q000187:drug effects; D002217:Carbachol / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004285:Dogs; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D023421:Models, Animal; D015394:Molecular Structure; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013997:Time Factors
chemical_list: D058667:Adrenergic beta-3 Receptor Agonists; D000318:Adrenergic beta-Agonists; D001565:Benzoates; D001713:Biphenyl Compounds; D002217:Carbachol; C010574:biphenyl