Booming large ring small molecule drugs

Text . . Liusir large ring small molecule drug is a hot spot in the field of pharmaceutical chemistry in the past 20 years, because the large ring structure in improving pharmacological activity and selectivity, perfecting the pharmaceutical effect is significant, and takes into account the microstructure combined with the target and the macro-nature of pharmacodynamics.
clinical large ring small molecule drugs are mostly composed of 12 to 20 atoms of cyclopeptides or endoesters, mainly used to treat infections, inflammation and tumors and other diseases, oral and injection dosage forms.
chain-like peptide ring synthesis ring peptide can increase the stability and biological activity of the drug, and is mainly artificial design synthesis;
1, Pfizer's Laura Tyniconi is a class of drugs developed by Pfizer for mesolytic lymphoma kinases for the treatment of mesolytic lymphoma and non-small cell lung cancer, which went on sale in 2011.
but clinically it has been found that there is severe resistance to the use of clostrini and that brain metastasis often occurs in tumor cells, indicating that clotinist is difficult to enter the central nervous system.
In order to overcome drug resistance and be able to pass through the blood-brain barrier, Pfizer found through structural biology analysis that ALK kinases in patients who were resistant to clotiniry showed multiple point mutations or insertions of amino acid residues such as L1196M, G1269A, and G1202R, which are residues of contact with keriteni; A comparative analysis of the crystal structure of the K-empty protein and the ALK-clotini complex found that the 2-bit chlorine atom of keratotine was too close to the niobium base of the G1269 skeleton (3.0 terp. ) , and the bit resistance effect forced the niobium base to reverse by 30 degrees , thus paying for the energy consumption of the image entropy , indicating that the binding of 2-chlorine was a disadvantage.
So the removal of 2-chlorine atoms as the starting point, the removal of 2-chlorine atoms found to be more active, 2 bits with other replacement base is still active, and the crystal structure shows that the compounds are "U"-shaped structure, suggesting that the head end of the fluorobenzene base and the tail end of the hetero-ring in space is close, thus designing the synthesis of the ring-shaped Lara tini.
single-bond rotation in the molecules behind the rings is also limited, which compensates for the combination of energy lost in the simplified structure and facilitates the entry into the brain through the blood-brain barrier, which was approved for listing in 2018.
2, Blainger Ingham's BI-4020 skin growth factor subject (EGFR) if the amino acid residue Ile19 is missing or Theu858 mutation, can lead to tumor cell proliferation, especially lung cancer.
although there are many EGFR kinase inhibitors on the market, the recurrence rate of lung cancer is higher after two years of drug use, mainly due to drug resistance caused by EGFR mutation.
In order to find the leading compounds with preliminary selectivity, the researchers screened the compounds with mutated EGFR and wild EGFR proteins, and the results showed that derivative 1 had better inhibitory activity on mutant EGFR (IC50 x 250 nmol/L to 2100 nmol/L), while no inhibition activity was found on wild EGFR or other kinases.
Remove the benzene ring F atoms of the compound, enzymatics and cellular activity are not affected; the end is replaced with benzene, the activity remains constant, but more selective; and the cocrystalline structure indicates that the end benzene ring is close to hydroxyl isobutyl as an active structure, thus linking it.
molecular simulation shows that the introduction of alkyl, and enzyme binding force enhancement, further optimized to get BI-4020.
3, Johnson and Johnson's important target for the treatment of viral hepatitis C is protease NS3, whose function is to crack structural proteins to mature, lysis products on NS3 inhibition.
product of NS5A/5BN at the cleavage connection point NS5A/5BN has a strong inhibitory activity on NS3, which is used as a starting point for the development of anti-hepatitis C drugs.
Under the guidance of structural and computational biology, the results of the structural relationship study found that the reduction of a peptide bond, N-end amino acetylation, the transformation of C-end for cyclopropione glycine and proline propranium methoxygenation of 2a; Improves liposuction, converts proline nuclei into cycloprene diacids, isopropyl into statins, and the rings are modified to replace the zirtine fragments and cyclopropyl ethylene 2b; c; then connect the vinyl fusion of 2c ring ecycline and C into a large ring compound 2d, and introduce sulfonamide group at the cyclopropyl base, which is connected to both sulfonyl and niobium, pulling electrons on both sides to make N-H have Weak acidity, simulated the original C-side of the carbapene base, and adjusted the polarity of the compound, used as sodium salts, and then modified the ring, to obtain a highly active and selective NS3 protease inhibitor to obtain the hepatitis C drug simpivir.
4, BMS FXIa inhibitor clotting is a bio-chemical cascading reaction, one of the enzymatic link is FXIa factor catalysis, is a trypsin-like serine protease, in the coagulase production process played a key role, and therefore the occurrence and maturation of blood clots is essential.
high levels of FXIa in the blood are at risk of myocardial infarction and deep vein thrombosis, while FXIa low expression causes less tendency to bleed, so FXIa inhibitors should be antithrombosis drugs with a low risk of bleeding.
BMS research found that open-chain molecule 3 has better inhibitory activity to FXIa, as a guide to further optimize the activity, pharmacy and materialization properties.
cocrystalline structure shows that the high activity of 3 is due to the involvement of multiple hemorracts in the binding with the FXIa enzyme activity center, the two benzene ring space is relatively close together, can be used as the formation of large ring points.
is connected to 12 and 13 yuan rings (n,1, 2) with alkyl or oxygen alkyl (X-O), the R of the mide ring may be H or Cl, and all synthetic compounds are less active than the lead of the chain 3.
the introduction of double bonds in the large ring, compound 3a anti-enzyme activity and anticoagulant effect significantly increased;
5, other cyclopeptide drugs can have different structural types, completely composed of amino acids cyclopeptides, can be N-end and C-end end connected to the ring peptide, such as cyclosporine A is 11 amino acids by the first and last by the peptide bond to form the largest ring, because mostly N-methyl amino acids, protease is relatively stable, is a rare oral cycloprotein.
cyclosporine A is used as an excretive drug for organ transplantation, however, the adverse reactions are large, and the modified voclosporin transforms only one amino acid side chain.
phase III clinical results showed that the adverse reactions of voclosporin were significantly lower than cyclosporine A, and had significant effects on lupus nephritis.
30 years ago, the study of peptide compounds was mostly focused on non-peptides and peptide simulations, with the in-depth understanding of the non-pharmacological and protein-protein interactions of many proteins, as well as the development of peptide chemistry and biological pharmacology, the direct development of peptide drugs has become an important field, of which pin-cured peptides are the platform technology developed in the past 20 years.
based on the intervention of MDM2-p53 protein-protein interactions, researchers synthesized p5314-29. α-helix fragments of hydrocarbon nail-curing peptides, design hydrocarbon-based nailing location to avoid binding points with MDM2, hydrocarbon rings span i, i-7, by round dichromatography, synthesis of 8 peptides in the stable α-helix configuration, wherein compound 4 and no hydrocarbon-based nail-solid peptide comparison, combined with MDM2 α-helix composition accounted for 85%, active Kd s 55 nmol. L-1, compared with 11% of the non-nail-cured active composition, increased activity by 7 times.
, because nail curing also improves the ability to cross the cell membrane, protecting the role of natural p53, cancer cells show apoptosis.
The first nail-cured peptide to enter clinical study is ALRN-6924, currently in phase II, a double inhibitor of p53-MDM2 and p53-MDMX, which is found by phage display of active peptides, made from hydrocarbon-based nails of i, i,7.
0.9 and 6.8nmol, respectively, for MDM2 and MDMX binding forces. L-1.
by blocking the combination of MDM2 to p53, which promotes the apoptosis of cancer cells.
progress of the organic synthesis reaction of small knots can occur C-C bonding under mild conditions, forming a large ring structure, which is the technical support for the study of large ring drugs.
Structural biology, molecular simulation and computational chemistry guide the design of large rings, designing the maintenance, size and elemental composition of large rings from microstructures, thus opening up new areas of drug creation and expanding the chemical space for the development of drugs with poor drugability and interventional protein-protein interactions. As an alternative large ring molecule, nail-cured peptides, although there are still many technical problems to be solved, so far there has been no successful pin-curing peptide market, but there is a potential development advantage, is a new growth point of peptide drugs, especially in the role of cytokines and signal conduction protein-protein interaction plays an important role.
Reference 1. Giordanetto F, Kihlberg J. Macrocyclic drugs and clinical candidates: What canmedicinal chemists learn from their properties? J Med Chem, 2014, 57:278-295.2 Johnson TW, Richardson PF, Bailey S, et al. Discovery of (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno) pyrazolo 5,11' -benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a macrocyclic resectionor of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) with preclinical brain exposure and broad-spectrumpot mutations . . . J Med Chem, 2014, 57: 4720-4744.3. Engelhardt H, Böse D, Petronczki M, et al. Start selective and rigidify: the discoverypath towards a next generation of EGFR tyrosine kinase resedors. J Med Chem, 2019, 62:10272-10293.4. Corte JR, Fang TA, Osuna H, et al. Structure-based design of macrocyclicfactor XIa resedors: discovery of the macrocyclicitye linker . J MedChem, 2017, 60: 1060-1075.5.Rancourt J, Cameron D, Gorys V, et al. Peptide-base resedors of thehepatitis C virus NS3 protease: structure-activity relationship at the C-terminal position. J Med Chem, 2004, 47: 2511-2422.6.Birsan T, Dambrin C, Freitag DG, et al. The novel calcineurin resor ISA247: a more potent immunosuppressant than cyclosporine in vitro. Transpl Int,2005, 17:767-771.