College school and corporate mind collide - he's Mibaratin.

Transverse vitamin A acid is the metabolic intermediate of vitamin A in the body, composed of hydrophobic group, hydrophilic group and conjugate chain, clinically used for the treatment of psoriasis and leukemia, but the stability of conjugate chain is poor, prone to polymerization and degeneration, coupled with strong stimulation of the argon base, limiting its use in clinical.
all-trans-dimensional A acid can also be isomed into 9-shun-dimensional A acid, although the biological function of the two is similar, but the binding receptor is different.
transverse a acid mainly binds to the viA acid receptor (RAR), 9-shun-dimensional A acid binds to the vIX receptor (RXR), and each of the two receptors has three subtypes, namely alpha, beta and gamma.
the University of Tokyo to analyze the highly active eusterised esters and aromatic stoic structures of psoriasis, it is speculated that conjugate polyene of viA acid can be replaced by benzene rings, and that a series of non-carbon atoms connected to participate in the conjugate system can be used to design a series of via benzoic acid derivatives.
1, amide derivatives design synthesis First benzene ring using amide bond (-NHCO-) connection, benzene ring with different alkyl or cyclic alkyl for single replacement, double replacement or three replacement, activity table below.
R is a small and medium-sized group, the compound is not active or weak activity, R is benzene or cyclic base and other large groups, there is no activity, R is two isopropyl or dibuedyl, the position is different, the number is different, the activity is different, the three strongest activity, of which 3,4-di-isopropyl compound 19 activity is stronger than the visor a acid;
2, 3,4-dipropyl-based ring-together Imagine that 4,4-di-ipropyl-based four methyls are ringed in different directions to obtain three derivatives.
compound 21 and 19 of the same number of carbon atoms, but no methyl, the activity disappears;
3, amide bond skeleton leap the amide bond-NHCO-converted into -CONH-to-conH-to-the-skeleton jump on the effect of compound activity.
the skeleton jump, the benzene ring did not replace the base or single replace the butyl activity disappeared, double replacement activity recovery, tetrahydroquinon has four methyl when the activity is 7.2 times the full transverse a acid.
results show that after the skeleton jumps, the structural relationship of derivatives is the same.
4, benzene ring or amide on the substitution further explored the benzene ring or amide nitrogen atom replacement on the effect of activity.
the introduction of replacement base in the adjacent is significantly reduced activity, may be due to the adjlocation effect is not conducive to the activity may be altered molecular conformation and conformationalal inactivation, which is the same as the previous 2 or 6 replacement activity disappear results;
move the argon base of the most active derivative from the opposite position to the interposition, the activity is reduced by 1000 times, possibly due to the lack of inter-position argon base involved in conjugate system.
5, skeleton to acrylic structure Compounds 23 and 29 only exist skeleton transformation, the effectiveness of inducing differentiation activity is relatively high, which indicates that there is also a large optimization space for the connecting base.
further transformed it into a propylene ketone structure for further optimization.
compared to the aforementioned amide derivatives, the phytol in the skeleton of chorketone was replaced with disopropyl or dibutyl, the activity was higher, and the activity of tetramethyl tetrahydrocoride was also relatively high.
different from amide derivatives, 6-bit substitute base (45-47) also has a higher activity, and stronger than viA acid.
this may be the cross conjugate of charketone allows a single bond to be twisted to a certain extent, maintaining the active conformation and avoiding the disturbance of neighbor (or forced) methyl.
6, flavonoids as the parent nuclear compound Charketone has different low-energy structure, charketone is the origin of flavonoids in plants, so the study of flavonoids as a derivative of the parent nucleus of the via acid.
the size, position and quantity of progesterone prothesis on the induced differentiation effect is the same as the aforementioned amine, amide-connected compounds and the structural relationship of charketone (structure and data omission), so this time only four methyl tetrahydroxanandfuranone as the parent nuclear representative compound.
compound 48 has a strong activity, 27 times the acid of the viA.
however, due to the structure of the dense three rings, the physical and chemical properties and drug-making properties of the potential problems, did not do in-depth study.
interesting is that the three-bit connectivity of flavonoids is still active.
7,compounds Trans-diphenethylene compounds ( class) are the aforementioned alymide or amide compounds of the electrons and other excretions, the difference is that theclass to the bond to connect the two benzene, amide is connected by p-to-thin conjugate. the number and size of the alkyl on the benzene ring
have the same effect on activity as the previous alymide or acrylic series of compounds.
interesting, compound 60 is the compound 57 double-bonded to reduce into a single-bonded benzene ring compound, the activity decreased by nearly a thousand times, can be interpreted as the loss of the double bond destroys the whole molecular conjugate.
8, the candidate compound and his mbaratin market finally identified the candidate drug as compound 29, has not yet found a combination of the drug properties, safety and physical properties of the various highly active compounds.
compound 29 in rats with a half-life t1/2 of 3.4 to 4.0h and tmax 2 to 4h, the metabolites are mainly hydroxylated at different positions in the lipid ring.
safety experiments showed that no abnormal behavior or death was observed in the subcutaneous injection of 50 mg kg-1 in rats.
compound 29 was developed by Dongguang Pharmaceuticals and named tamibaroten.
clinical trials showing that oral applications can treat acute early childhood leukemia and were launched in Japan and the United States in 2005.
summary meta-barbin was developed by the University of Tokyo to simulate the distribution and molecular conformation of all-trans-dimensional A acid, and developed with the structural relationship of drug chemistry.
carefully read the published literature, can clearly perceive the university's research model, such as the design of different skeletons, all need to repeatedly explore the benzene ring no replacement base, single replacement base, double replacement base, three replacement base, replace the size of the base on the effect of biological activity, and prove its activity is poor or inactive, before follow-up research.
actually tried once is enough, although from the perspective of new drug research and development, many processes are repetitive, but the essence of the university is teaching and educating people, so the systematic and integrity of academic research in the first place, will not be in order to quickly obtain products and contrary to the original intention.
this concept is also common in our country's colleges and universities.
but there is a big gap in the development of its other sister drug, Besharotin.
will detail the besartatin development process in the next article for space reasons.
Reference1. Retinobenzoic acids. Structure-activity relationships of the aromatic sainswith retinoidal activity. J Med Chem 2. Retinobenzoic acids. Structure-activity relationships of chalcone-4-carboxylic acids and flavone-4'-carboxylic acids. J Med Chem 3. Retinobenzoic acids. Structure-activity relationships of retinoidalazobeen-4-carboxylic acids and stilbene-4-carboxylic acids. J Med Chem 4. Retinobenzoic acids. Conformation of the aromatic sydd sydd yn ystod. Importance of transamide structure for the activity. J Med Chem 5. Structure-activity relationships of retinoidal azobeen-4-carboxylic acidsand stilbene-4-carboxylic acids. J Med Chem.