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Although the inhibitory activity of derivative 7 on c-Met kinase is weak Ki=3.
83μmol·L-1, its ligand efficiency is better than 5 (LE=0.
29) due to its low molecular weight, but the lipophilic efficiency is reduced ( LipE=0.
35)
.
Therefore, the polar side chain can be introduced at the hydroxyl of the benzene ring of the derivative, and the morpholine ethylene group can be introduced to obtain the derivative 8.
The activity is slightly increased (Ki=2.
45 μmol·L-1), but the ligand rate is reduced.
Imitating the fragment of derivative 4, we get 9, the inhibitory activity and lipophilic efficiency are improved, Ki=0.
46μmol·L-1, LE=0.
24, LipE=3.
70
.
Substituent transformation of dichlorophenyl group and methyl substitution of linker methylene group
In order to investigate the influence of the substituents on the ring on the active Ki and the lipophilic efficiency LipE, one or more, the same or different halogens were introduced on the benzene ring, and the linking chain was substituted or unsubstituted with methyl groups, and a series of general formulas were synthesized.
The activity measurement of the derivative of 10 found that the activity of derivative 11 is the highest, the activity parameters for c-Met enzyme are: Ki=0.
012μmol·L-1, LipE=4.
82; the activity parameters for c-Met cells are: IC50 =0.
020μmol·L-1, LipE=4.
60
.
Transformation of 5-benzene ring
According to the crystal structure of the complex, 5-phenyl is bound to the narrow hydrophobic gap formed by Tyr1159, Ile1084, and Gly1163.
This requires the planarity of the aromatic ring connected at the 5-position of the aminopyridine and the extension of the group connected to the aryl group.
Into the solvent phase
.
In addition, the amide fragment in 11 has left the hydrophobic cleft and entered the water phase, suggesting that the extended hydrophilic fragment does not need to be connected by an amide bond
.
Replacing the 5-benzene ring with a five-membered nitrogen-containing aromatic ring can increase water solubility.
For example, the cLogD of a compound containing 5-pyrazole or imidazole is 2 units lower than the corresponding benzene compound, and the twist angle is smaller, which increases the coplanarity.
Conducive to integration
.
The connection mode of the aminopyridine and the pyrazole ring has a great influence on the activity.
For example, the activity of compounds 12 and 13 and the LipE value are very different
.
Structural biology shows that the position of the nitrogen atom of the pyrazole ring of 12 makes the c-Met residues Met1160 and Ile1084 oriented adjacent to the pyrazole ring, which is not conducive to the hydrogen bonding of aminopyridine, and the pyrazole ring is in the enzyme protein.
In order to occur hydrophobic-hydrophobic interaction, the dehydration of the lone electron pair of the N atom is an unfavorable enthalpy change; and the 13 N atoms all enter the water phase without the above-mentioned adverse effects, so the activity is high 12.
Enzyme or cell activity is increased by 30-40 times
.
The N-methylation of compound 13 produces 14 more active, suggesting that the carbon chain containing polar groups can be drawn from this N atom to improve the active water solubility
.
Optimization of N-substituted pyrazole compounds
In view of the fact that the structure of compound 9 contains basic groups extending to the water phase to improve the activity and lipophilic efficiency, the smallest possible basic fragments, such as chain alkyl groups, amines, and azetidines, are also introduced on the pyrrole ring system.
, Tetrahydropyrrole, piperidine, etc.
, to increase activity and improve pharmacy and pharmacokinetic properties
.
While selecting compounds with high activity and high lipophilic efficiency, the stability to human liver microsomes is also evaluated.
15 and 16 are preferred from the representative compounds, especially because of the high activity and better metabolic stability of 16 Sex, identified as a drug candidate
.
The success of crizotinib
The pyrazole series of compounds prepared by the aforementioned optimization process contain chiral carbon atoms, and the activity is measured with mixed samples
.
The optimized compound 16 was split into optically active substances, and the activity measurement showed that the activity of R-configuration component 17 was stronger than that of RS and S configuration, and its enzyme and cell inhibitory activities were Ki = 0.
002μmol·L-1 and IC50=0.
008μmol·L-1, named crizotinib
.
It only took 4 years for crizotinib to be approved by the FDA in 2007.
Its emergence is another major breakthrough in individualized treatment.
Its clinical status surpasses conventional chemotherapy and is the current ALK.
Standard medicine for patients with positive advanced non-small cell lung cancer
.
references
1 Cui JR, et al.
4-Aryl substituted indolinones.
WO02/055517
2 Cui JR, et al.
5-Aralkylsulfonyl-3-(pyrrol-2-ylmethylidene)-2-indolinones as kinaseinhibitors.
WO 02/096361
3 Cui JR, Tran DM, Shen H, et al.
Structurebased drug design of crizotinib (PF-02341066), a potent and selective dualinhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK).
J Med Chem, 2011, 54: 6342-6363
4 Roberts PJ.
Clinical use of crizotinib for the treatment of non-small cell lung cancer.
Biologics, 2013, 7: 91–101.