Chemistry

3.1 - 3.5 - cimetidine (total)

3.1 - 3.5 - cimetidine (total)



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Improved H.2-Selectivities

To the pKaTo reduce the value of burimamide, an electron withdrawing group would have to be added to the side chain, for example by adding an electronegative element to the side chain. However, this atom should have as little effect as possible on the rest of the molecule, i.e. the first atom to be tested was sulfur.

Sulfur is a relatively good isosteric atom for a methylene group because both units have approximately equal van der Waals radii and similar bond angles. Only the C-S bond is slightly longer than the C-C bond, which elongates the entire molecule a little (~ 15%).

The exchanged methylene group was in the next but one position to the imidazole ring. This position was chosen for purely pragmatic reasons, as a synthetic route was already known for this compound.

The hoped-for humiliation of the pKaThe value of the compound thiaburimamide obtained resulted in a value of pKa = 6.25 and increased antagonistic activity. This result supported the assumption that reducing the level of the ionic tautomer would have beneficial effects on binding to the receptor and on activity.

Thiaburimamide was synthesized to favor the non-ionic tautomers over the ionic. The question then arose as to which of the two non-ionic tautomers is preferred for binding to the receptor.

When examining histamine, it can be seen that the nitrogen atom closer to the side chain is more exposed to the inductive effect of the side chain and is therefore less basic because of its lower electron density.

This effect, which is also present in thiaburimamide, should be reinforced by an electron donating group at position 4 by increasing the basic character of the nitrogen atom at position 3. However, this group was not allowed to interfere with normal binding to the receptor.

On the basis of previous studies it was already known that 4-methyl-histamine is a powerful agonist and highly selective for the H.2Receptor was. Therefore, a methyl group was chosen as the electron donating substituent. The compound metiamide obtained actually showed increased activity.

Interestingly, the effect of the methyl group could be an observed increase in the pKa-Value compared to burimamide from 6.25 to 6.80 more than compensate.

For comparison, 4-methylburimamide was synthesized. However, the introduction of the methyl group did not lead to an increase in the activity here. Of the pKaValue increased to 7.80 whereby the proportion of the ionic form rose to over 70%.

Metiamide was designed and synthesized using a streamlined approach to favorite one of the tautomers. This method is called dynamic structure-activity analysis.

During the development of metiamide, it was suggested that the increased activity was due to conformal properties, as the thioether group showed increased flexibility.

This flexibility could be influenced by the methyl group in such a way that the desired orientation of the imidazole ring in the receptor is supported.

It was found, however, that the oxygen analogue has a much lower activity, although the electron-withdrawing effect of the oxygen atom is similar to that of a sulfur atom and the ether group has bond angles and lengths similar to that of a methylene group. In this regard, the oxygen analog has better properties than the sulfur analog. However, the oxygen atom is much smaller, more hydrophilic and more basic than the sulfur atom.

The low activity of oxaburamide can be explained in different ways. For example, conformal flexibility could be limited or the oxygen atom could form a hydrogen bond with the receptor or an intramolecular hydrogen bond.

Metiamide is ten times more active than burimamide and promised to be the first compound to become a potential drug for treating gastric ulcers. Unfortunately, after the initiation into clinical research, some of the 700 patients treated showed kidney damage and a reduction in white blood cells, so clinical investigations with metiamide had to be discontinued.


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