Novel NAMPT enzyme agonist and preparation and application thereof
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A technology of activating effect and aromatic compounds, applied in the fields of medicinal chemistry, enzymology and pharmacology, it can solve the problem of not having intellectual property rights, and achieve the effect of good cell protection
Active Publication Date: 2022-07-08
TSINGHUA UNIV
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Problems solved by technology
In recent years, there have been more than ten clinical trials in progress, but the dose of NAD precursor needs to be taken is very large, further studies on pharmacokinetics and safety are needed, and the results of clinical trials have not yet been published (E.Verdin, NAD( +)in aging,metabolism,and neurodegeneration.Science350,1208-1213(2015).;H.Zhang et al.,NAD(+)repletion improves mitochondria and stem cell function and enhances life span inmice.Science352,1436-1443(2016) ; G.Wang et al., P7C3 neuroprotective chemicals function by activating the rate-limiting enzyme in NAD salt. Cell158, 1324-1334(2014))
On the other hand, these NAD precursors are naturally occurring metabolites over which no one has intellectual property rights
Method used
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Embodiment 1
[0068] Example 1. Preparation of 2-(2-(tert-butyl)phenoxy)-N-(4-hydroxyphenyl)acetamide
[0071] 2-(tert-Butyl)phenol (0.92 g, 6 mmol) and Cs 2 CO 3 (3.9 g, 12 mmol) was dissolved in 6 mL of acetone, then tert-butyl 2-bromoacetate (2.39 g, 12 mmol) was added and the reaction was allowed to overnight at 55°C. After the reaction, the mixture was filtered and the filtrate was concentrated and purified by silica gel chromatography to obtain tert-butyl 2-(2-(tert-butyl)phenoxy)acetate as a white solid. 1 H NMR (400MHz, CDCl 3 )δ7.33(dd,J=7.7,1.7Hz,1H),7.18(ddd,J=8.0,7.3,1.7Hz,1H),6.95(td,J=7.5,1.2Hz,1H),6.74(dd , J=8.1, 1.2Hz, 1H), 4.56(s, 2H), 1.52(s, 9H), 1.45(s, 9H).
[0072] 1.2 2-(2-(tert-butyl)phenoxy)acetic acid
[0073] 2-(2-(tert-Butyl)phenoxy)tert-butyl acetate (0.92 g, 6 mmol) was dissolved in 4 mL of dichloromethane, then 2 mL of trifluoroacetic acid was slowly added dropwise. After stirring the r...
Embodiment 2
[0076] Example 2. Preparation of 2-(2-(tert-butyl)phenoxy)-N-phenylacetamide
[0077]
[0078] Referring to Example 1 (replace 4-aminophenol in step 1.3 with aniline), white solid Example 2 was obtained. 1 HNMR (400MHz, CDCl 3 )δ8.40(s,1H),7.66-7.58(m,2H),7.40(td,J=7.3,1.6Hz,3H),7.28-7.23(m,1H),7.22-7.16(m,1H) ,7.05(td,J=7.6,1.2Hz,1H),6.93(dd,J=8.2,1.2Hz,1H),4.71(s,2H),1.54(s,9H). 13 C NMR (101MHz, CDCl 3 )δ166.43,155.80,138.12,136.99,129.21,127.64,127.30,124.85,122.31,119.69,113.21,68.07,34.77,30.17.
Embodiment 3
[0079] Example 3. Preparation of 2-(2-(tert-butyl)phenoxy)-N-(3-hydroxyphenyl)acetamide
[0080]
[0081] Referring to Example 1 (replace 4-aminophenol in step 1.3 with 3-aminophenol), white solid Example 3 was obtained. 1 H NMR (400MHz, CDCl 3 )δ8.49(s,1H),7.97(t,J=2.2Hz,1H),7.40(dd,J=7.9,1.7Hz,1H),7.35(s,1H),7.24(q,J=8.2 Hz, 2H), 7.05 (td, J=7.6, 1.2Hz, 1H), 6.92 (dd, J=8.2, 1.1Hz, 1H), 6.70 (ddd, J=20.4, 8.0, 2.2Hz, 2H), 4.73 (s,2H),1.52(s,9H). 13 C NMR (101MHz, CDCl 3 )δ167.29,157.32,155.58,138.09,137.72,130.04,127.67,127.35,122.47,113.29,112.34,110.82,107.16,67.82,34.75,30.18.
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Abstract
The invention provides a novel NAMPT enzyme agonist as well as preparation and application thereof. The structural formula is shown as a formula I or a formula II. According to the invention, the NAMPT agonist NAT is screened from a chemical small molecule library, and the NAT shows a good cell protection effect and shows a good anti-neurodegenerative curative effect in a neurodegenerative animal model. Combination of NAT and enzyme is studied, then multiple rounds of structure optimization are performed according to chemical structure characteristics and enzyme activity characteristics of NAT, and a relatively clear structure-function relationship is obtained. The invention not only lays a foundation for providing an innovative medicine for resisting aging and neurodegenerative diseases, but also theoretically provides concept verification for enhancing the NAMPT enzyme activity to play an important role in neuroprotection.
Description
technical field [0001] The invention relates to the fields of medicinal chemistry, enzymology and pharmacology, in particular to a novel NAMPT enzyme agonist and its preparation and use. Background technique [0002] 1. Pharmacological importance and challenges of anti-aging and neurodegenerative disease drugs [0003] Aging is a rather complex process, and in recent years, aging-related diseases, especially neurodegenerative diseases, have been on the rise globally. China is rapidly entering an aging society. The intractable nature of neurodegenerative diseases and the need for special care for patients have brought a heavy burden to families, society and the country. For a country like China with a large population and an increasingly aging population, how to effectively control, delay aging and treat neurodegenerative diseases has become a daunting task for domestic researchers at present and even in the next few decades. [0004] Although the incidence of neurodegenera...
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