Matrix metal protease inhibitor and medicinal use thereof
A kind of use, amino technology, applied in the field of new matrix metalloproteinase inhibitors, can solve the problems of low bioavailability, poor selectivity of hydroxamic acids, etc.
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Embodiment 1
[0018] Example 1: Synthesis of benzamide ilomastat derivatives
[0019]
[0020] Using the method explored by Liu Keliang et al., using isocaproyl chloride as the starting material to synthesize compound 2 through multiple non-reactions;
[0021] Compound 1: Take a two-necked bottle, N 2 Protect, vacuumize, first add compound 2, stir and dissolve with anhydrous DCM, add EDCI·HCl and DMAP, react for 1 hour, add phenylenediamine substitute, stir overnight, TLC detection (DCM:MeOH=10:1) raw material Whether the reaction is complete. After the reaction was completed, it was concentrated under reduced pressure, extracted with DCM, saturated NaHCO 3 , water, saturated NaCl solution, and the organic layer was anhydrous NaSO 4 Dry, concentrate, and purify on a silica gel column (DCM:MeOH=30:1-15:1) to obtain the target compound (1a-1h) in powder form.
[0022] N-Deshydroxy-N-(2-aminophenyl)ilomastat (1a)
[0023] White powder, yield 36.23%. 1 H NMR (400MHz, CD 3 OD) δppm: 7....
Embodiment 2
[0038] Example 2: Inhibition of benzamide ilomastat derivatives on MMP-2 and MMP-9
[0039] A fluorescent drug detection kit was used to screen the inhibitory activity of the synthesized compounds on MMP-2 and MMP-9. In this method, a quenched fluorescent peptide is used to screen the corresponding inhibitors. MMP-2 Fluorescent Drug Kit (BML-AK409-0001) and MMP-9 Fluorescent Drug Kit (BML-AK411-0001) (purchased from Enzo Life Sciences company), the screening principle of the kit: quenched fluorescent polypeptide substrate OmniMMP TM fluorgenic substrate Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH 2 [Mca=(7-methoxycoumarin-4-yl)-acetyl; Dpa=N-3-(2,4-dinitrophenyl)-L-α-β-diaminopropionyl]; the fluorescence properties of Mca can be inhibited by the Dpa group, but MMPs can break the quenched fluorescent polypeptide into two chains at Gly-Leu, so that the fluorescence of Mca can be visualized, and then the screening of MMPI inhibitors can be carried out;
[0040] Pretreatment: first tha...
Embodiment 3
[0047] Embodiment 3: the mensuration of the fat-water partition coefficient logP of compound 1a
[0048] Take 20ml of water and 20ml of n-octanol in Erlenmeyer flasks with stoppers (3 copies for each group), vortex for 5min, shake at room temperature for 24h, place in a separating funnel, let stand for 24h, separate the liquid, and take Add about 1.15mg E-1 (1.83mg Ilomastat) to 1ml of the upper layer (saturated n-octanol layer) (so that the concentration of the drug in both n-octanol and aqueous phases is less than 0.01mol / l), and vortex for 5min. Mix with 1ml of n-octanol-saturated aqueous phase, vortex for 5min, shake at room temperature for 24h, centrifuge at 3500rpm for 15min, take 100μL respectively in the sample tube, in 30% acetonitrile + 1% TFA (Ilomastat: 25% acetonitrile + 1% TFA ) under HPLC analysis. Measured: 1a: logP=1.912±0.006; and Ilomastat: logP=1.036±0.005, the results show that benzamide analogue 1a has certain druggability.
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