title: Discovery of Novel Indazole Derivatives as Orally Available β3-Adrenergic Receptor Agonists Lacking Off-Target-Based Cardiovascular Side Effects.
abstract: We previously discovered that indazole derivative 8 was a highly selective β3-adrenergic receptor (β3-AR) agonist, but it appeared to be metabolically unstable. To improve metabolic stability, further optimization of this scaffold was carried out. We focused on the sulfonamide moiety of this scaffold, which resulted in the discovery of compound 15 as a highly potent β3-AR agonist (EC50= 18 nM) being inactive to β1-, β2-, and α1A-AR (β1/β3, β2/β3, and α1A/β3> 556-fold). Compound 15 showed dose-dependent β3-AR-mediated responses in marmoset urinary bladder smooth muscle, had a desirable metabolic stability and pharmacokinetic profile (Cmaxand AUC), and did not obviously affect heart rate or mean blood pressure when administered intravenously (3 mg/kg) to anesthetized rats. Thus, compound 15 is a highly potent, selective, and orally available β3-AR agonist, which may serve as a candidate drug for the treatment of overactive bladder without off-target-based cardiovascular side effects.
authors.affiliation: Pharmaceutical Research Center, Asahi Kasei Pharma Corporation , 632-1, Mifuku, Izunokuni, Shizuoka 410-2321, Japan.
authors.forename: Yasuhiro
authors.identifier: 0000-0002-5988-2912
authors.initials: Y
authors.lastname: Wada
authors.affiliation: Pharmaceutical Research Center, Asahi Kasei Pharma Corporation , 632-1, Mifuku, Izunokuni, Shizuoka 410-2321, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Nakano
authors.affiliation: Pharmaceutical Research Center, Asahi Kasei Pharma Corporation , 632-1, Mifuku, Izunokuni, Shizuoka 410-2321, Japan.
authors.forename: Akifumi
authors.initials: A
authors.lastname: Morimoto
authors.affiliation: Pharmaceutical Research Center, Asahi Kasei Pharma Corporation , 632-1, Mifuku, Izunokuni, Shizuoka 410-2321, Japan.
authors.forename: Ken-Ichi
authors.initials: KI
authors.lastname: Kasahara
authors.affiliation: Pharmaceutical Research Center, Asahi Kasei Pharma Corporation , 632-1, Mifuku, Izunokuni, Shizuoka 410-2321, Japan.
authors.forename: Takahiko
authors.initials: T
authors.lastname: Hayashi
authors.affiliation: Pharmaceutical Research Center, Asahi Kasei Pharma Corporation , 632-1, Mifuku, Izunokuni, Shizuoka 410-2321, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Takada
authors.affiliation: Pharmaceutical Research Center, Asahi Kasei Pharma Corporation , 632-1, Mifuku, Izunokuni, Shizuoka 410-2321, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Suzuki
authors.affiliation: Pharmaceutical Research Center, Asahi Kasei Pharma Corporation , 632-1, Mifuku, Izunokuni, Shizuoka 410-2321, Japan.
authors.forename: Michiko
authors.initials: M
authors.lastname: Niwa-Sakai
authors.affiliation: Pharmaceutical Research Center, Asahi Kasei Pharma Corporation , 632-1, Mifuku, Izunokuni, Shizuoka 410-2321, Japan.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Ohashi
authors.affiliation: Pharmaceutical Research Center, Asahi Kasei Pharma Corporation , 632-1, Mifuku, Izunokuni, Shizuoka 410-2321, Japan.
authors.forename: Mutsuhiro
authors.initials: M
authors.lastname: Mori
authors.affiliation: Molecular Profiling Research Center for Drug Discovery (molprof), National Institute of Advanced Industrial Science and Technology (AIST) , 2-4-7 Aomi, Koto-ku, Tokyo 135-0064, Japan.|Division of Biomedical Science, Faculty of Medicine, University of Tsukuba , 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Takatsugu
authors.initials: T
authors.lastname: Hirokawa
authors.forename: Satoshi
authors.identifier: 0000-0001-7850-8064
authors.initials: S
authors.lastname: Shuto
mesh_terms: D000284:Administration, Oral; D058667:Adrenergic beta-3 Receptor Agonists / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D002319:Cardiovascular System / Q000187:drug effects*; D004285:Dogs; D055808:Drug Discovery; D006801:Humans; D007191:Indazoles / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats
chemical_list: D058667:Adrenergic beta-3 Receptor Agonists; D007191:Indazoles