- Discovery of Novel Indazole Derivatives as Orally Available β3-Adrenergic Receptor Agonists Lacking Off-Target-Based Cardiovascular Side Effects
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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 (Cmax and 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.
- Wada, Yasuhiro,Nakano, Seiji,Morimoto, Akifumi,Kasahara, Ken-ichi,Hayashi, Takahiko,Takada, Yoshio,Suzuki, Hiroko,Niwa-Sakai, Michiko,Ohashi, Shigeki,Mori, Mutsuhiro,Hirokawa, Takatsugu,Shuto, Satoshi
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p. 3252 - 3265
(2017/05/05)
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- INDAZOLE ANALOGUE
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[Objective] To provide a drug that selectively stimulates the β3-adrenergic receptors, particularly a drug capable of preferentially stimulating the β3-adrenergic receptors over the α1-adrenergic receptors. This drug can be used in the treatment and prevention of diabetes, obesity, hyperlipidemia, depression, cholelithiasis, diseases caused by biliary hyperkinesia, diseases caused by hyperfunction of the gastrointestinal tract, interstitial cystitis, overactive bladder or urinary incontinence, diseases associated with decreased lacrimation, and the like. [Solution] Indazole analogs represented by the general formula (I) or a salt thereof. Drugs that contains these indazole analogs or a salt thereof as the active ingredient.
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