In 2022,Scarneo, Scott; Hughes, Philip; Freeze, Robert; Yang, Kelly; Totzke, Juliane; Haystead, Timothy published an article in ACS Chemical Biology. The title of the article was 《Development and Efficacy of an Orally Bioavailable Selective TAK1 Inhibitor for the Treatment of Inflammatory Arthritis》.Application of 27489-62-9 The author mentioned the following in the article:
Selective targeting of TNF in inflammatory diseases such as rheumatoid arthritis (RA) has provided great therapeutic benefit to many patients with chronic RA. Although these therapies show initially high response rates, their therapeutic benefit is limited over the lifetime of the patient due to the development of antidrug antibodies that preclude proper therapeutic benefits. As a result, patients often return to more problematic therapies such as methotrexate or hydroxychloroquine, which carry long-term side effects. Thus, there is an unmet medical need to develop alternative treatments enabling patients to regain the benefits of selectively targeting TNF functions in vivo. The protein kinase TAK1 is a critical signaling node in TNF-mediated intracellular signaling, regulating downstream NF-κβ activation, leading to the transcription of inflammatory cytokines. TAK1 inhibitors have been developed but have been limited in their clin. advancement due to the lack of selectivity within the human kinome and, most importantly, lack of oral bioavailability. Using a directed medicinal chem. approach, driven by the cocrystal structure of the TAK1 inhibitor takinib, we developed HS-276 (I), a potent (Ki = 2.5 nM) and highly selective orally bioavailable TAK1 inhibitor. Following oral administration in normal mice, HS-276 is well tolerated (MTD >100 mg/Kg), displaying >95% bioavailability with μM plasma levels. The in vitro and in vivo efficacy of HS-276 showed significant inhibition of TNF-mediated cytokine profiles, correlating with significant attenuation of arthritic-like symptoms in the CIA mouse model of inflammatory RA. Our studies reinforce the hypothesis that TAK1 can be safely targeted pharmacol. to provide an effective alternative to frontline biol.-based RA therapeutics.trans-4-Aminocyclohexanol(cas: 27489-62-9Application of 27489-62-9) was used in this study.
trans-4-Aminocyclohexanol(cas: 27489-62-9) belongs to anime. The methylamines occur in small amounts in some plants. Many polyfunctional amines (i.e., those having other functional groups in the molecule) occur as alkaloids in plants—for example, mescaline, 2-(3,4,5-trimethoxyphenyl)ethylamine; the cyclic amines nicotine, atropine, morphine, and cocaine; and the quaternary salt choline, N-(2-hydroxyethyl)trimethylammonium chloride, which is present in nerve synapses and in plant and animal cells.Application of 27489-62-9
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