1221178-86-4Relevant articles and documents
Discovery of Novel Indazole Derivatives as Highly Potent and Selective Human β3-Adrenergic Receptor Agonists with the Possibility of Having No Cardiovascular Side Effects
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
, p. 6048 - 6057 (2015/08/24)
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.
INDAZOLE DERIVATIVES
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Page/Page column 46, (2010/06/22)
Compounds represented by the Formula (A-1) and the Formula (1) or salt thereof are provided. The compounds represented by the Formula (A-1) and the Formula (1) or salt thereof have a β3 adrenergic receptor agonist activity, and therefore are useful as an agent for the prevention and treatment of diabetes, obesity, hyperlipidemia, depression, biliary stone, a disorder derived from hyperactivity of biliary tract, a disorder derived from hyperactivity of digestive tract, interstitial cystitis, overactive bladder, urinary incontinence or a disorder derived from decreased tear secretion, etc.