title: Discovery of Novel Indazole Derivatives as Highly Potent and Selective Human β3-Adrenergic Receptor Agonists with the Possibility of Having No Cardiovascular Side Effects.
abstract: Novel indazole derivatives were prepared and evaluated for their biological activity and cardiovascular safety profile as human β3-adrenergic receptor (AR) agonists. Although the initial hit compound 5 exhibited significant β3-AR agonistic activity (EC50 = 21 nM), it also exhibited agonistic activity at the α1A-AR (EC50 = 219 nM, selectivity: α1A/β3 = 10-fold). The major metabolite of 5, which was an oxidative product at the indazole 3-methyl moiety, gave a clue to a strategy for improvement of the selectivity for β3-AR agonistic activity versus α1A-AR agonistic activity. Thus, modification of the 3-substituent of the indazole moiety effectively improved the selectivity to develop compound 11 with potent β3-AR agonistic activity (EC50 = 13 nM) and high selectivity (α1A/β3 = >769-fold). Compound 11 was also inactive toward β1 and β2-ARs and showed dose dependent β3-AR mediated relaxation of marmoset urinary bladder smooth muscle, while it did not obviously affect heart rate or blood pressure (iv, 3 mg/kg) in anesthetized rats.
authors.affiliation: †Pharmaceutical Research Center, Asahi Kasei Pharma Corporation, 632-1, Mifuku, Izunokuni-shi, Shizuoka 410-2321, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Wada
authors.affiliation: †Pharmaceutical Research Center, Asahi Kasei Pharma Corporation, 632-1, Mifuku, Izunokuni-shi, Shizuoka 410-2321, Japan.
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Shirahashi
authors.affiliation: †Pharmaceutical Research Center, Asahi Kasei Pharma Corporation, 632-1, Mifuku, Izunokuni-shi, Shizuoka 410-2321, Japan.
authors.forename: Taisuke
authors.initials: T
authors.lastname: Iwanami
authors.affiliation: †Pharmaceutical Research Center, Asahi Kasei Pharma Corporation, 632-1, Mifuku, Izunokuni-shi, Shizuoka 410-2321, Japan.
authors.forename: Masami
authors.initials: M
authors.lastname: Ogawa
authors.affiliation: †Pharmaceutical Research Center, Asahi Kasei Pharma Corporation, 632-1, Mifuku, Izunokuni-shi, 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-shi, 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-shi, Shizuoka 410-2321, Japan.
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Kasahara
authors.affiliation: †Pharmaceutical Research Center, Asahi Kasei Pharma Corporation, 632-1, Mifuku, Izunokuni-shi, Shizuoka 410-2321, Japan.
authors.forename: Eiichi
authors.initials: E
authors.lastname: Tanaka
authors.affiliation: †Pharmaceutical Research Center, Asahi Kasei Pharma Corporation, 632-1, Mifuku, Izunokuni-shi, 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-shi, 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-shi, Shizuoka 410-2321, Japan.
authors.forename: Mutsuhiro
authors.initials: M
authors.lastname: Mori
authors.forename: Satoshi
authors.initials: S
authors.lastname: Shuto
mesh_terms: D058667:Adrenergic beta-3 Receptor Agonists / Q000009:adverse effects / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D002319:Cardiovascular System / Q000187:drug effects; D006801:Humans; D007191:Indazoles / Q000009:adverse effects / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D058667:Adrenergic beta-3 Receptor Agonists; D007191:Indazoles