Journal of Medicinal Chemistry p. 6048 - 6057 (2015)
Update date:2022-08-02
Topics:
Wada, Yasuhiro
Shirahashi, Hiromitsu
Iwanami, Taisuke
Ogawa, Masami
Nakano, Seiji
Morimoto, Akifumi
Kasahara, Ken-Ichi
Tanaka, Eiichi
Takada, Yoshio
Ohashi, Shigeki
Mori, Mutsuhiro
Shuto, Satoshi
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.
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